title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Survival outcome and reduction rate of Ki-67 between pre- and post-neoadjuvant chemotherapy in breast cancer patients with non-pCR. | The research question of this investigation is whether the reduction rate of Ki-67 after neoadjuvant chemotherapy (NAC) could indicate a survival in patients with non-pCR. A total of 455 patients had received NAC, and subsequent surgery was analyzed retrospectively. Patients with non-pCR were divided into three subgroups according to Ki-67 change: High-reduction (the absolute value of Ki-67 was reduced by >80 % compared with that prior to NAC), Low-reduction (the absolute value of Ki-67 was reduced by 0-80 % compared with that prior to NAC), and Increase group (the absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. pCR was achieved in 93 patients (20.4 %). In patients with non-pCR, the median reduction rate of Ki-67 was 60 %. A total of 15 % of patients were in the High-reduction, 63 % in the Low-reduction, and 22 % in the Increase group. The median follow-up period was 64.5 months. The 5-year RFS rates among the three groups were significantly different (p < 0.0001), and the differences were also observed in the HER2 (p = 0.033), triple-negative (p = 0.034), and luminal-like subtypes (p = 0.001). Patients in the High-reduction group showed comparable RFS to that of patients with pCR (p = 0.363). In patients with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of cancer subtypes. Therefore, patients who are non-pCR but who achieve a high reduction of Ki-67 can be expected to have a favorable prognosis similar to that of patients with pCR. | 25,106,660 | [
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Pollution biomonitoring in the Bizerte lagoon (Tunisia), using combined chemical and biomarker analyses in grass goby, Zosterisessor ophiocephalus (Teleostei, Gobiidae). | In this study, biological responses and contaminant levels in biological tissues were investigated in grass goby fish specimens (Zosterisessor ophiocephalus) collected from five stations in a moderately polluted ecosystem, namely the Bizerte lagoon on the north coast of Tunisia. The following biomarkers were measured: muscular acetylcholinesterase (AChE), hepatic ethoxyresorufin-O-deethylase (EROD), glutathione-S-transferase (GST), catalase (CAT), lipoperoxidation (TBARS), condition factor (CF), and hepatosomatic index (HSI). These measurements were taken in parallel with the content of Organochlorine pesticides (OCPs), Polychlorinated biphenyls (PCBs), Polycyclic aromatic hydrocarbons (PAHs) and trace metals (As, Cr, Cu, Mn, Pb, V, Zn, Ag, Cd, Co and Ni) in muscle tissue. Total PAH concentrations ranged from 20.09 ± 0.68 to 105.77 ± 42.58 ng g(-1) dw, PCB from 33.19 ± 6.25 to 126.28 ± 7.37 ng g(-1) dw, OCP from 11.26 ± 1.62 to 19.17 ± 2.06 ng g(-1) dw, and metals from 107.83 ± 1.83 to 187.21 ± 2.00 mg/kg dw. The highest levels of pollutants and biomarkers were observed at station S1, located in the Bizerte channel. Elevated EROD, GST and CAT activities, as well as TBARS levels in liver were positively correlated with tissue contaminant levels at station S1. Significant negative correlations were also found between hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDTs) body burden with AChE activity in muscle at station S2. The integration of biological responses and contaminant tissue content indicated that certain areas of the Bizerte lagoon, notably station S1, are significantly impacted by various human activities, which likely represent a threat for aquatic wildlife. On the basis of these results, and due to its ecological characteristics, the grass goby appears a suitable indicator species for pollution biomonitoring in coastal marine areas along the Mediterranean Sea. | 25,106,667 | [
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CD18 deficiency evolving to megakaryocytic (M7) acute myeloid leukemia: case report. | Leukocyte adhesion deficiency type 1 (LAD 1 - CD18 deficiency) is a rare disease characterized by disturbance of phagocyte function associated with less severe cellular and humoral dysfunction. The main features are bacterial and fungal infections predominantly in the skin and mucosal surfaces, impaired wound healing and delayed umbilical cord separation. The infections are indolent, necrotic and recurrent. In contrast to the striking difficulties in defense against bacterial and fungal microorganisms, LAD 1 patients do not exhibit susceptibility to viral infections and neoplasias. The severity of clinical manifestations is directly related to the degree of CD18 deficiency. Here, a 20 year-old female presenting a partial CD18 deficiency that developed a megakaryocytic (M7) acute myeloid leukemia is described for the first time. The clinical features of the patient included relapsing oral thrush due to Candida, cutaneous infections and upper and lower respiratory tract infections, followed by a locally severe necrotic genital herpetic lesion. The patient's clinical features improved for a period of approximately two years, followed by severe bacterial infections. At that time, the investigation showed a megakaryocytic acute myeloid leukemia, treated with MEC without clinical improvement. The highly aggressive evolution of the leukemia in this patient suggests that adhesion molecules could be involved in the protection against the spread of neoplastic cells. | 25,106,692 | [
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Thioredoxin-1 redox signaling regulates cell survival in response to hyperoxia. | The most common form of newborn chronic lung disease, bronchopulmonary dysplasia (BPD), is thought to be caused by oxidative disruption of lung morphogenesis, which results in decreased pulmonary vasculature and alveolar simplification. Although cellular redox status is known to regulate cellular proliferation and differentiation, redox-sensitive pathways associated with these processes in developing pulmonary epithelium are unknown. Redox-sensitive pathways are commonly regulated by cysteine thiol modifications. Therefore two thiol oxidoreductase systems, thioredoxin and glutathione, were chosen to elucidate the roles of these pathways on cell death. Studies herein indicate that thiol oxidation contributes to cell death through impaired activity of glutathione-dependent and thioredoxin (Trx) systems and altered signaling through redox-sensitive pathways. Free thiol content decreased by 71% with hyperoxic (95% oxygen) exposure. Increased cell death was observed during oxygen exposure when either the Trx or the glutathione-dependent system was pharmacologically inhibited with aurothioglucose (ATG) or buthionine sulfoximine, respectively. However, inhibition of the Trx system yielded the smallest decrease in free thiol content (1.44% with ATG treatment vs 21.33% with BSO treatment). Although Trx1 protein levels were unchanged, Trx1 function was impaired during hyperoxic treatment as indicated by progressive cysteine oxidation. Overexpression of Trx1 in H1299 cells utilizing an inducible construct increased cell survival during hyperoxia, whereas siRNA knockdown of Trx1 during oxygen treatment reduced cell viability. Overall, this indicated that a comparatively small pool of proteins relies on Trx redox functions to mediate cell survival in hyperoxia, and the protective functions of Trx1 are progressively lost by its oxidative inhibition. To further elucidate the role of Trx1, potential Trx1 redox protein-protein interactions mediating cytoprotection and cell survival pathways were determined by utilizing a substrate trap (mass action trapping) proteomics approach. With this method, known Trx1 targets were detected, including peroxiredoxin-1as well as novel targets, including two HSP90 isoforms (HSP90AA1 and HSP90AB1). Reactive cysteines within the structure of HSP90 are known to modulate its ATPase-dependent chaperone activity through disulfide formation and S-nitrosylation. Whereas HSP90 expression is unchanged at the protein level during hyperoxic exposure, siRNA knockdown significantly increased hyperoxic cell death by 2.5-fold, indicating cellular dependence on HSP90 chaperone functions in response to hyperoxic exposure. These data support the hypothesis that hyperoxic impairment of Trx1 has a negative impact on HSP90-oxidative responses critical to cell survival, with potential implications for pathways implicated in lung development and the pathogenesis of BPD. | 25,106,706 | [
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GP surgeons: what are they? An audit of GP surgeons in South Australia. | In many parts of Australia where there is no access to local specialist services, procedural services are provided by local GPs. Within the range of procedural skills offered, a small group of GPs is able to provide surgery. Unlike other procedural areas, there remains no defined training or assessment pathway for GP surgeons. Support from specialist colleagues is variable and continuing education arbitrary. The result is a somewhat ill-defined group that is poorly understood by credentialing bodies, government, medical defence organisations and training colleges. This study aims to describe the scope of practice, initial training and ongoing support and education for GP surgeons currently practising in South Australia. Seventeen semistructured interviews were undertaken with self-identified GP surgeons (74% response rate). Areas explored included demographics, scope of practice, initial training and ongoing support and education. Content and thematic analysis was used to identify common responses and themes. The amount of initial training varied among participants, with a mean duration of training of 20 months. Initial assessment of competency for the majority of participants was assessment by a supervisor (10/17). The most common procedures undertaken were caesarean sections (94% of participants) and grafts and flaps (94%). The most common continuing professional development was clinical attachments (27%) and assisting visiting specialists or colleagues (17%). This study demonstrates a wide variation in training, scope of practice and continuing education for GPs performing surgery, highlighting the effects of a self-regulated system. There is a trend towards an increased level of training; however, engagement in continuing education remains low. Further work is needed to define this group, to enable successful planning of future training and education to support this group in rural areas. | 25,106,725 | [
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Neighborhood Ethnic Composition and Problem Drinking Among Older Mexican American Men: Results from the Hispanic Established Populations for the Epidemiologic Study of the Elderly. | Ethnic enclaves may be protective for health. This study investigates the effects of neighborhood co-ethnic density on problem drinking among older Mexican American men. Probability sample of 2,086 community-dwelling Mexican Americans aged 75 or older drawn in 2004-2005 residing in communities in Arizona, California, Colorado, New Mexico and Texas. Problem drinking was found among 15.3 % of men (n = 350). For each percent increase in neighborhood percent Mexican American, men had 2 % lower odds of problem drinking [odds ratio (OR) 0.98; P < 0.05]. U.S. born men had lower odds of problem drinking (OR 0.40; P < 0.05) compared with foreign born men, while English language use was associated with greater odds of problem drinking (OR 2.14; P < 0.05). Older Mexican American men in neighborhoods with low levels of co-ethnic density, the foreign born, and those with English language facility had an increased likelihood of problem drinking. | 25,106,726 | [
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Preterm small-for-gestational age children: predictive role of gestational age for mental development at the age of 2 years. | The aim of the study was to compare the cognitive development of very low birth weight (VLBW) preterm SGA children and preterm AGA children at the age of 2 years. The hypothesis was that SGA children are at an additional risk for deficits in cognitive function. Additionally, the impact of neonatal risk factors and the parents' profession on the early cognitive development was analysed. Cognitive function of 107 preterm infants with a gestational age of 24-35 weeks was assessed with the Mental Bayley Scales of Infant Development at the age of 2 years (mean±SEM). The results of SGA (n=38) and AGA (n=69) children were compared as well as neonatal risk factors and parental education. There was a linear regression between the Mental Bayley Scales result and gestational age for preterm infants with a gestational age of 24-32 weeks. SGA and AGA children did not differ significantly in their cognitive function at the age of 2 years. A strong association was found between the parents' profession and cognitive development. Among the neonatal risk factors, bronchopulmonary dysplasia was a strong predictor of mental development. Cognitive development of two-year-old preterm children with a gestational age of 24-32 weeks was mainly related to their gestational age. Being born preterm and small for gestational age was not additionally associated with cognitive deficits at the age of 2 years. The parents' profession had a significant impact on the cognitive development. The role of the parents' profession on the early development of preterm infants should be elucidated in further studies. | 25,106,733 | [
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Comprehensive study of hydrostatic pressure treated human umbilical cord blood cells via response surface method. | Amelioration of the survival parameters of cryopreserved samples after thawing has already been addressed through several techniques including vitrification to avoid the formation of ice cores. However, this approach cannot be followed in the case of samples with higher volumes. Hydrostatic pressure (HP) treatment has been proven to increase some qualifying parameters (e.g., motility, insemination efficiency) of certain biological samples. Accordingly, the preparation of umbilical cord blood (UCB) samples through an active (mechanical) pre-stressing process to increase the survival rate of cryopreserved samples can be regarded as a novel strategy that calls for basic experimental studies. The goal of our study was to assess the effects of HP treatment on the qualifying parameters (DNA fragmentation by agarose gel electrophoresis and capillary electrophoresis, Total Nucleotide Cell (TNC) count, CD34+/CD45+ count, and superoxide dismutase activity (SOD) of human umbilical cord blood (UCB) derived cells). The experimental arrangement was set to provide data for response-surface analysis to take into account the common effects of the individual variables of pressure and time exposure. 3D visualization of experimental data revealed that 50-min long HP treatment at 12.5 MPa can significantly (α = 0.05) enhance white blood cell (WBC) and CD34+/CD45+ cell counts. However no DNA fragmentation was observed even at higher pressures, SOD activity was triggered over 15.0 MPa. As a conclusion, HP treatment may contribute to the optimal cryopreservation of UCB cells by significantly increasing WBC and CD34+/CD45+ cell counts without adverse effects neither on DNA stability nor on triggering SOD activity. | 25,106,745 | [
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TDS exposure project: relevance of the total diet study approach for different groups of substances. | A method to validate the relevance of the Total Diet Study (TDS) approach for different types of substances is described. As a first step, a list of >2800 chemicals classified into eight main groups of relevance for food safety (natural components, environmental contaminants, substances intentionally added to foods, residues, naturally occurring contaminants, process contaminants, contaminants from packaging and food contact materials, other substances) has been established. The appropriateness of the TDS approach for the different substance groups has then been considered with regard to the three essential principles of a TDS: representativeness of the whole diet, pooling of foods and food analyzed as consumed. Four criteria were considered for that purpose (i) the substance has to be present in a significant part of the diet or predominantly present in specific food groups, (ii) a robust analytical method has to be available to determine it in potential contributors to the dietary exposure of the population, and (iii) the dilution impact of pooling and (iv) the impact of everyday food preparation methods on the concentration of the substance are assessed. For most of the substances the TDS approach appeared to be relevant and any precautions to be taken are outlined. | 25,106,751 | [
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Phylogenetic analyses on the diversity of Aspergillus fumigatus sensu lato based on five orthologous loci. | One hundred isolates of Aspergillus fumigatus sensu lato mainly from China, as well as from Australia, France, India, Indonesia, Ireland, UK, and USA were analyzed to infer their sequence types (STs) and population diversity based on partial calmodulin, calcineurin regulatory subunit B, beta-tubulin, cytochrome C and calcineurin catalytic subunit A genes as well as their mating types, using ClonalFrame, Structure and MEGA software. Our results inferred 48 STs and showed that most of the STs or lineages evolved independently and without clear population structure among them. Whereas one lineage was recognized that could be a true population and in which one clade might diverge into another distinct lineage, namely, a cryptic species, A. neoellipticus. In addition, we found that mutation, parasexual, and sexual recombination could, respectively, play specific roles in the evolution of these fungi. Our results also showed that MAT1-1/MAT1-2 mating type ratios of A. fumigatus sensu lato was biased to nearly 1:1.4 (20/28) when clone-corrected, but when not clone-corrected, the ratio of MAT1-1/MAT1-2 was so biased as near 1:2 (35/65), which might mean that isolates with MAT1-2 are in the process of losing sexual ability preceding those with MAT1-1. | 25,106,755 | [
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Role of Brønsted acid in selective production of furfural in biomass pyrolysis. | In this work, the role of Brønsted acid for furfural production in biomass pyrolysis on supported sulfates catalysts was investigated. The introduction of Brønsted acid was shown to improve the degradation of polysaccharides to intermediates for furfural, which did not work well when only Lewis acids were used in the process. Experimental results showed that CuSO4/HZSM-5 catalyst exhibited the best performance for furfural (28% yield), which was much higher than individual HZSM-5 (5%) and CuSO4 (6%). The optimum reaction conditions called for the mass ratio of CuSO4/HZSM-5 to be 0.4 and the catalyst/biomass mass ratio to be 0.5. The recycled catalyst exhibited low productivity (9%). Analysis of the catalysts by Py-IR revealed that the CuSO4/HZSM-5 owned a stronger Brønsted acid intensity than HZSM-5 or the recycled CuSO4/HZSM-5. Therefore, the existence of Brønsted acid is necessary to achieve a more productive degradation of biomass for furfural. | 25,106,779 | [
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Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. | Marrow stimulation for the treatment of osteochondral lesions of the talus (OLTs) is controversial in patients with poor prognostic factors of OLTs. Currently, mesenchymal stem cells (MSCs) are expected to biologically augment the treatment of OLTs. To compare the clinical and magnetic resonance imaging (MRI) outcomes between an injection of MSCs with marrow stimulation and marrow stimulation alone in patients with OLTs. Cohort study; Level of evidence, 3. A total of 49 patients (50 ankles) with OLTs underwent follow-up MRI after arthroscopic treatment. Among these 50 ankles, 26 underwent marrow stimulation alone (conventional group), and 24 underwent marrow stimulation with an injection of a stromal vascular fraction (SVF) containing MSCs (MSC group). Clinical outcomes were evaluated according to the visual analog scale (VAS) for pain, American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, and Tegner activity scale. The magnetic resonance observation of cartilage repair tissue (MOCART) score was used for the MRI evaluation of repaired lesions. The mean VAS score, AOFAS score, and Tegner score improved from 7.1 ± 1.2, 68.5 ± 5.6, and 3.4 ± 0.6 to 3.9 ± 0.8, 78.3 ± 4.9, and 3.5 ± 0.8, respectively, in the conventional group and from 7.1 ± 0.8, 67.7 ± 4.7, and 3.4 ± 0.5 to 3.2 ± 0.8, 83.3 ± 7.0, and 3.9 ± 0.7, respectively, in the MSC group. All clinical outcomes, including the VAS, AOFAS, and Tegner scores, improved significantly in the MSC group compared with the conventional group (P = .003, .009, and .041, respectively). There was a significant difference (P = .037) in the mean MOCART score between the conventional and MSC groups (49.4 ± 16.6 vs 62.1 ± 21.8, respectively), and significant correlations of the MOCART score with clinical outcomes were found in both groups (P < .05). Patient age (≥46.1 years), large lesion size (≥151.2 mm(2)), and the presence of subchondral cysts were associated with a worse MOCART score in the conventional group (P = .015, .004, and .013, respectively) but not in the MSC group. Clinical and MRI outcomes of an injection of an SVF containing MSCs with marrow stimulation were encouraging, compared with marrow stimulation alone, for the treatment of OLTs. Therefore, an injection of an SVF containing MSCs with marrow stimulation should be considered as a treatment for OLTs, even when poor prognostic factors, including older age, large-sized lesion, or the presence of subchondral cysts, exist. | 25,106,781 | [
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The effectiveness of student-run organizations within global health promotion initiatives. | This commentary describes a student-led project that distributed long-lasting insecticide-treated nets in Masaka, Uganda. The role of student-led initiatives in global health promotion projects is also discussed. A survey of 213 net recipients was conducted after a 12-month period to evaluate malaria prevention knowledge, and net use and maintenance. Only 4.7% of recipients could not recall any malaria prevention methods. Seventy percent of pregnant women and 86.5% of children under five slept under a net the previous night. Only two households (0.9%) no longer possessed a net, and nets were not used in 2.3% of houses. Household observation revealed 17.4% of nets had at least one problem that would compromise effectiveness. Student-led projects can play an important role in effectively preventing malaria. However coordination with existing programs, targeting hard-to-access groups, and training of students overcomes some common limitations of such student-led initiatives. | 25,106,790 | [
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Natural polyphenols enhance stability of crosslinked UHMWPE for joint implants. | Radiation-crosslinked UHMWPE has been used for joint implants since the 1990s. Postirradiation remelting enhances oxidative stability, but with some loss in strength and toughness. Vitamin E-stabilized crosslinked UHMWPE has shown improved strength and stability as compared with irradiated and remelted UHMWPE. With more active phenolic hydroxyl groups, natural polyphenols are widely used in the food and pharmaceutical industries as potent stabilizers and could be useful for oxidative stability in crosslinked UHMWPE. We asked whether UHMWPE blended with polyphenols would (1) show higher oxidation resistance after radiation crosslinking; (2) preserve the mechanical properties of UHMWPE after accelerated aging; and (3) alter the wear resistance of radiation-crosslinked UHMWPE. The polyphenols, gallic acid and dodecyl gallate, were blended with medical-grade UHMWPE followed by consolidation and electron beam irradiation at 100 kGy. Radiation-crosslinked virgin and vitamin E-blended UHMWPEs were used as reference materials. The UHMWPEs were aged at 120 °C in air with oxidation levels analyzed by infrared spectroscopy. Tensile (n = 5 per group) and impact (n = 3 per group) properties before and after aging as per ASTM F2003 were evaluated. The wear rates were examined by pin-on-disc testing (n = 3 per group). The data were reported as mean ± SDs. Statistical analysis was performed by using Student's t-test for a two-tailed distribution with unequal variance for tensile and impact data obtained with n ≥ 3. A significant difference is defined with p < 0.05. The oxidation induction time of 100 kGy UHMWPE was prolonged to 144 hours with 0.05 wt% dodecyl gallate and 192 hours with 0.05 wt% gallic acid compared with 48 hours for 0.05 wt% vitamin E-blended UHMWPE. Accelerated aging of these polyphenol-blended UHMWPEs resulted in ultimate tensile strength of 50.4 ± 1.4 MPa and impact strength of 53 ± 5 kJ/m(2) for 100 kGy-irradiated UHMWPE with 0.05 wt% dodecyl gallate, for example, in comparison to 51.2 ± 0.7 MPa (p = 0.75) and 58 ± 5 kJ/m(2) (p = 0.29) before aging. The pin-on-disc wear rates of 100 kGy-irradiated UHMWPE with 0.05 wt% dodecyl gallate and 0.05 wt% gallic acid were 2.29 ± 0.31 and 1.65 ± 0.32 mg/million cycles, comparable to 1.68 ± 0.25 and 2.05 ± 0.22 mg/million cycles for 100 kGy-irradiated virgin and 0.05 wt% vitamin E-blended UHMWPE. Based on the sample numbers tested in this study, polyphenols appear to effectively enhance the oxidation stability without altering the mechanical properties or pin-on-disc wear rate of radiation-crosslinked UHMWPE. Crosslinked UHMWPE with natural polyphenols with improved oxidative stability and low wear may find clinical application in joint implants. | 25,106,800 | [
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Positive symptoms and water diffusivity of the prefrontal and temporal cortices in schizophrenia patients: a pilot study. | The development of diffusion tensor imaging (DTI) has provided information about microstructural changes in the brain. Most DTI studies have focused on white matter (WM). Few DTI studies have examined the gray matter (GM) in schizophrenia and, to date, there has been no attempt to identify the relationship between water diffusivity and symptom severity in schizophrenia. The present study aimed to examine microstructural deficits in the dorsal prefrontal cortex (DPFC) and temporal cortex in schizophrenia patients using fractional anisotropy (FA) and water diffusivity. This study also explored the relationship between DTI measurements and psychotic symptoms. Magnetic resonance imaging (MRI) and DTI were used to study 19 schizophrenia patients and 19 healthy controls. Fractional anisotropy, axial diffusivity, radial diffusivity, and regional volumes were measured in the prefrontal cortex and temporal cortex. On DTI measurements, patients showed increased axial and radial diffusivities in the prefrontal cortex and temporal cortex, but they did not demonstrate any difference in fractional anisotropy and regional volumes. Additionally, axial and radial diffusivities were significantly correlated with positive symptom scores in all regions of interest. These results indicate that water diffusivity measurements, including axial and radial diffusivities, can be used to identify microstructural changes in the gray matter in schizophrenia that may be related to symptom severity. | 25,106,804 | [
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Unraveling the mechanism underlying the glycosylation and methylation of anthocyanins in peach. | Modification of anthocyanin plays an important role in increasing its stability in plants. Here, six anthocyanins were identified in peach (Prunus persica), and their structural diversity is attributed to glycosylation and methylation. Interestingly, peach is quite similar to the wild species Prunus ferganensis but differs from both Prunus davidiana and Prunus kansueasis in terms of anthocyanin composition in flowers. This indicates that peach is probably domesticated from P. ferganensis. Subsequently, genes responsible for both methylation and glycosylation of anthocyanins were identified, and their spatiotemporal expression results in different patterns of anthocyanin accumulation in flowers, leaves, and fruits. Two tandem-duplicated genes encoding flavonoid 3-O-glycosyltransferase (F3GT) in peach, PpUGT78A1 and PpUGT78A2, showed different activity toward anthocyanin, providing an example of divergent evolution of F3GT genes in plants. Two genes encoding anthocyanin O-methyltransferase (AOMT), PpAOMT1 and PpAOMT2, are expressed in leaves and flowers, but only PpAOMT2 is responsible for the O-methylation of anthocyanins at the 3' position in peach. In addition, our study reveals a novel branch of UGT78 genes in plants that lack the highly conserved intron 2 of the UGT gene family, with a great variation of the amino acid residue at position 22 of the plant secondary product glycosyltransferase box. Our results not only provide insights into the mechanisms underlying anthocyanin glycosylation and methylation in peach but will also aid in future attempts to manipulate flavonoid biosynthesis in peach as well as in other plants. | 25,106,821 | [
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[Misuse of opioid analgesics. An internet analysis]. | Apart from the prescribed administration and indications for pain relief, opioids are also used for unintended purposes. Information for misuse is circulated on the internet. In order to analyze the abuse of opioids and opiates,which are only available by prescription, defined search keywords were entered into the search engine of a German language internet forum on drugs in 2010 and 2013 and the results were evaluated. Items to be assessed and analyzed were the frequency of naming various substances and (in the first analysis only) aspects of their incorporation as well as user reports on various aspects of use (e.g. drug procurement, administration, effects and side effects). Tramadol was the most frequently quoted opioid followed by codeine, tilidine, morphine and oxycodone. Other opioids were named in only 10 % of the entries. Oral intake was the most frequently mentioned mode of administration followed by parenteral and nasal routes. These findings can support caregivers to identify unintended use of opioids and to increase awareness of the most frequently used opioids and modes of administration. | 25,106,826 | [
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Is neutrophil/lymphocyte ratio predict to short-term mortality in acute cerebral infarct independently from infarct volume? | Neutrophil/lymphocyte ratio (NLR) is related with increased mortality in both myocardial infarction and acute ischemic stroke. It remains unclear whether NLR is a simple marker of ischemic infarct volume or an independent marker of stroke mortality. The aim of this study is to investigate the relationship of NLR with infarct volume and short-term mortality in acute ischemic stroke (AIS). This retrospective study included 151 patients with first AIS that occurred within 24 hours of symptom onset. Patients were screened from the hospital's electronic record system by using International Classification of Diseases code (G 46.8). NLR was calculated as the ratio of neutrophils to lymphocytes. Short-term mortality was defined as 30-day mortality. A total 20 of 151 patients died during follow-up. Both NLR and infarct volume of nonsurvived group were significantly higher than survived group (P < .05). Infarct volume, NLR, and National Institutes of Health Stroke Scale (NIHSS) were independent predictors of the mortality in Cox regression analysis. The optimal cutoff value for NLR as a predictor for short-term mortality was determined as 4.81. NLR displayed a moderate correlation with both NIHSS and Glasgow Coma Scale (P < .01). NLR values were significantly higher in the highest infarct volume tertile than both in the lowest volume tertile and midtertile of infarct volume (P = .001). NLR at the time of hospital admission maybe a predictor of short-term mortality independent from infarct volume in AIS patients. NLR should be investigated in future prospective trials investigating AIS. | 25,106,834 | [
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Metazoan parasite communities of catfishes (Teleostei: Siluridae) in Benin (West Africa). | The need for more precise information on the effect of dry season on fish parasite communities in Benin lead us to undergo a focus during this season in one of the major sites of collection fry by fish farmers.Metazoan parasites were then inventoried in 166 specimens of catfishes which constituted of C larias gariepinus, Clarias ebriensis, Synodontis schall, Synodontis nigrita, and Chrysichthys nigrodigitatus (Teleostei: Siluridae). Those fishes were collected from fishermen of Agonlin-Lowé at the side of Oueme River in south Benin from November 2011 to March 2012. In total, 12 parasite species were listed comprising three Monogena (Gyrodactylus sp., Synodontella sp., and Protoancylodiscoides chrysichthes), three Cestoda (Stoeksia pujehuni, Lytocestus sp., and Cestode indeterminate), five Nematoda (Paracamallanus cyathopharynx, Procamallanus laevionchus, Cithariniella petterae, Synodontisia thelastomoides, and nematode indeterminate), and one indeterminated Copepod species. Total infestation rate varied between 83.87 and 100% for the different fish species. This was high but independent of fish sex (χ(2) = 1.669, df = 4, nonsignificant). The highest mean intensity and mean abundance were, respectively, 44 and 13.33. Monogenea and Nematoda have elevated frequency of dominance, and their presence in the host is significantly correlated (r = -0.999; p < 0.05). Clariids were highly infected by Nematoda. Except for P. laevionchus and Proteoancylodiscoides, respectively, in C. gariepinus and in C. nigrodigitatus, the parasites showed clumped distribution. The component community diversity, as measured by the Shannon index (H'), revealed that S. schall had the most parasite diversity. | 25,106,838 | [
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Age-dependent changes in Porphyromonas gingivalis and Prevotella species/phylotypes in healthy gingiva and inflamed/diseased sub-gingival sites. | Early colonisation of oral surfaces by periodontal pathogens presents a significant risk factor for subsequent development of destructive disease affecting tissues that support the dentition. The aims of the present study were to establish the age-dependent relationship between sub-gingival profiles of 22 Prevotella species/phylotypes in children, adolescents and adults from an isolated Aboriginal community and, further, to use this information to identify Prevotella species that could serve as microbial risk indicators. DNA isolated from sub-gingival plaque samples (three healthy sites and three inflamed/diseased sites) from adults, adolescents and children was screened for Porphyromonas gingivalis load and 22 Prevotella species/phylotypes by species-specific PCR. A noticeable feature in adolescents was the marked increase in colonisation by P. gingivalis across all test sites. The mean number of Prevotella species/phylotypes colonising inflamed/diseased sub-gingival sites increased with age. Progressive partitioning of selected Prevotella species/phylotypes to healthy or inflamed/diseased sites was evident. Prevalence of Prevotella intermedia, Prevotella oral clone P4PB_24 and Prevotella oris increased significantly with age in diseased sites. Similarly, significant age-dependent increase in colonisation of healthy as well as inflamed/diseased sub-gingival sites was apparent for Prevotella oralis, Prevotella multiformis, Prevotella denticola, Prevotella strain P4P_53 and Prevotella oral clone BR014. Early colonisation of children by P. gingivalis, P. intermedia and Prevotella oral clone P4PB_24 provides indication of risk for subsequent development of periodontal disease. In the present study, the complexity of Prevotella species within gingival sites is explored as a basis for evaluating contribution of Prevotella species to disease. | 25,106,846 | [
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Overexpression of recombinant infectious bursal disease virus (IBDV) capsid protein VP2 in the middle silk gland of transgenic silkworm. | Infectious bursal disease virus (IBDV) is the causative agent of a highly contagious disease affecting young chickens and causes serious economic losses to the poultry industry worldwide. Development of subunit vaccine using its major caspid protein, VP2, is one of the promising strategies to protect against IBDV. This study aim to test the feasibility of using silkworm to produce recombinant VP2 protein (rVP2) derived from a very virulent strain of IBDV (vvIBDV). A total of 16 transgenic silkworm lines harboring a codon-optimized VP2 gene driven by the sericin1 promoter were generated and analyzed. The results showed that the rVP2 was synthesized in the middle silk gland of all lines and secreted into their cocoons. The content of rVP2 in the cocoon of each line was ranged from 0.07 to 16.10 % of the total soluble proteins. The rVP2 was purified from 30 g cocoon powders with a yield of 3.33 mg and a purity >90 %. Further analysis indicated that the rVP2 was able to tolerate high temperatures up to 80 °C, and exhibited specific immunogenic activity in mice. To our knowledge, this is the first report of overexpressing rVP2 in the middle silk gland of transgenic silkworm, which demonstrates the capability of silkworm as an efficient tool to produce recombinant immunogens for use in new vaccines against animal diseases. | 25,106,848 | [
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Stem-loop binding protein is required for retinal cell proliferation, neurogenesis, and intraretinal axon pathfinding in zebrafish. | In the developing retina, neurogenesis and cell differentiation are coupled with cell proliferation. However, molecular mechanisms that coordinate cell proliferation and differentiation are not fully understood. In this study, we found that retinal neurogenesis is severely delayed in the zebrafish stem-loop binding protein (slbp) mutant. SLBP binds to a stem-loop structure at the 3'-end of histone mRNAs, and regulates a replication-dependent synthesis and degradation of histone proteins. Retinal cell proliferation becomes slower in the slbp1 mutant, resulting in cessation of retinal stem cell proliferation. Although retinal stem cells cease proliferation by 2 days postfertilization (dpf) in the slbp mutant, retinal progenitor cells in the central retina continue to proliferate and generate neurons until at least 5dpf. We found that this progenitor proliferation depends on Notch signaling, suggesting that Notch signaling maintains retinal progenitor proliferation when faced with reduced SLBP activity. Thus, SLBP is required for retinal stem cell maintenance. SLBP and Notch signaling are required for retinal progenitor cell proliferation and subsequent neurogenesis. We also show that SLBP1 is required for intraretinal axon pathfinding, probably through morphogenesis of the optic stalk, which expresses attractant cues. Taken together, these data indicate important roles of SLBP in retinal development. | 25,106,852 | [
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The rice WUSCHEL-related homeobox genes are involved in reproductive organ development, hormone signaling and abiotic stress response. | The WUSCHEL-related homeobox (WOX) genes are important transcription regulators participated in plant development processes. Rice (Oryza sativa L.) genome encodes at least 13 WOX members. In this study, a systematic microarray-based gene expression profiling of eleven WOX genes was performed for the whole life cycle of rice at 16 different tissues/organs of MH63 (rice indica cultivar), which included eight reproductive organs and eight vegetative tissues. The results demonstrated that four genes (OsWUS, OsNS1/OsNS2, OsWOX3 and OsWOX9A) were specifically expressed in panicle and endosperm development, and six genes (OsWOX5, OsWOX9B, OsWOX9D, OsWOX11, OsWOX12A and OsWOX12B) were preferentially expressed in seeds (72h after imbibitions) during root emergence or growth. In situ hybridization analysis revealed differential transcript levels of OsWOX4, OsWOX5, OsWOX9A and OsWOX12B during panicle development and embryogenesis. Results of qRT-PCR showed that expression of four rice WOX genes (OsWOX5, OsWOX11, OsWOX12B and OsWOX12A) was up- or down-regulated by plant hormones (auxin, cytokinin and gibberellin). More interestingly, most WOX genes were responsive to abiotic stress stimuli of drought, salt and cold. The molecular studies presented here will further provide insight in understanding the functions of rice WOX gene family in rice development, hormone signaling, and abiotic stress response. | 25,106,855 | [
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Drosophila COP9 signalosome subunit 7 interacts with multiple genomic loci to regulate development. | The COP9 signalosome protein complex has a central role in the regulation of development of multicellular organisms. While the function of this complex in ubiquitin-mediated protein degradation is well established, results over the past few years have hinted that the COP9 signalosome may function more broadly in the regulation of gene expression. Here, using DamID technology, we show that COP9 signalosome subunit 7 functionally associates with a large number of genomic loci in the Drosophila genome, and show that the expression of many genes within these loci is COP9 signalosome-dependent. This association is likely direct as we show CSN7 binds DNA in vitro. The genes targeted by CSN7 are preferentially enriched for transcriptionally active regions of the genome, and are involved in the regulation of distinct gene ontology groupings including imaginal disc development and cell-cycle control. In accord, loss of CSN7 function leads to cell-cycle delay and altered wing development. These results indicate that CSN7, and by extension the entire COP9 signalosome, functions directly in transcriptional control. While the COP9 signalosome protein complex has long been known to regulate protein degradation, here we expand the role of this complex by showing that subunit 7 binds DNA in vitro and functions directly in vivo in transcriptional control of developmentally important pathways that are relevant for human health. | 25,106,867 | [
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ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway. | Low-density lipoprotein receptor (LDLR) mRNA is unstable, but is stabilized upon extracellular signal-regulated kinase (ERK) activation, possibly through the binding of certain proteins to the LDLR mRNA 3'-untranslated region (UTR), although the detailed mechanism underlying this stability control is unclear. Here, using a proteomic approach, we show that proteins ZFP36L1 and ZFP36L2 specifically bind to the 3'-UTR of LDLR mRNA and recruit the CCR4-NOT-deadenylase complex, resulting in mRNA destabilization. We also show that the C-terminal regions of ZFP36L1 and ZFP36L2 are directly phosphorylated by p90 ribosomal S6 kinase, a kinase downstream of ERK, resulting in dissociation of the CCR4-NOT-deadenylase complex and stabilization of LDLR mRNA. We further demonstrate that targeted disruption of the interaction between LDLR mRNA and ZFP36L1 and ZFP36L2 using antisense oligonucleotides results in upregulation of LDLR mRNA and protein. These results indicate that ZFP36L1 and ZFP36L2 regulate LDLR protein levels downstream of ERK. Our results also show the usefulness of our method for identifying critical regulators of specific RNAs and the potency of antisense oligonucleotide-based therapeutics. | 25,106,868 | [
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Quantification of DNA-associated proteins inside eukaryotic cells using single-molecule localization microscopy. | Development of single-molecule localization microscopy techniques has allowed nanometre scale localization accuracy inside cells, permitting the resolution of ultra-fine cell structure and the elucidation of crucial molecular mechanisms. Application of these methodologies to understanding processes underlying DNA replication and repair has been limited to defined in vitro biochemical analysis and prokaryotic cells. In order to expand these techniques to eukaryotic systems, we have further developed a photo-activated localization microscopy-based method to directly visualize DNA-associated proteins in unfixed eukaryotic cells. We demonstrate that motion blurring of fluorescence due to protein diffusivity can be used to selectively image the DNA-bound population of proteins. We designed and tested a simple methodology and show that it can be used to detect changes in DNA binding of a replicative helicase subunit, Mcm4, and the replication sliding clamp, PCNA, between different stages of the cell cycle and between distinct genetic backgrounds. | 25,106,872 | [
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Lupinalbin A as the most potent estrogen receptor α- and aryl hydrocarbon receptor agonist in Eriosema laurentii de Wild. (Leguminosae). | Eriosema laurentii De Wild. (Leguminosae) is a plant used in Cameroon against infertility and gynecological or menopausal complaints. In our previous report, a methanol extract of its aerial parts was shown to exhibit estrogenic and aryl hydrocarbon receptor agonistic activities in vitro and to prevent menopausal symptoms in ovariectomized Wistar rats. In order to determine the major estrogen receptor α (ERα) agonists in the extract, an activity-guided fractionation was performed using the ERα yeast screen. To check whether the ERα active fractions/compounds also accounted for the aryl hydrocarbon receptor (AhR) agonistic activity of the crude methanol extract, they were further tested on the AhR yeast screen. This study led to the identification of 2'-hydroxygenistein, lupinalbin A and genistein as major estrogenic principles of the extract. 2'-hydroxygenistein and lupinalbin A were, for the first time, also shown to possess an AhR agonistic activity, whereas genistein was not active in this assay. In addition, it was possible to deduce structure-activity relationships. These results suggest that the identified compounds are the major active principles responsible for the estrogenic and AhR agonistic activities of the crude methanol extract of the aerial parts of Eriosema laurentii. | 25,106,881 | [
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Polymorphisms in endothelial nitric oxide synthase gene in early and late severe preeclampsia. | Preeclampsia (PE) is characterized by hypertension and proteinuria, occurring after the 20th week of pregnancy in women who have had no previous symptoms. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Clinically, it is important to diagnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher. Recently, the gestational age (GA) of the onset of PE has led to the classification of this disease as early (GA <34 weeks) and late (GA ≥34 weeks). Several genetic polymorphisms affecting endothelial nitric oxide synthase (eNOS) levels or function were described, including G894T (Glu298Asp), VNTR b/a (variable-number 27-bp tandem repeat) and T-786C (promoter) polymorphisms. Thus, the aim of this study was to compare the distribution of G894T, VNTR b/a and T-786C polymorphisms and their haplotypes in Brazilian early and late sPE, as well as in normotensive pregnant. A total of 201 women were evaluated, 53 with early sPE, 45 with late sPE and 103 as normotensive pregnant women. The frequency of 894T allele was higher in late sPE vs normotensive pregnant, and 894TT genotype was higher in late sPE vs early sPE and normotensive pregnant. For VNTR b/a polymorphism, higher frequencies of aa genotype and a allele were observed in early sPE vs late sPE and normotensive pregnant. Besides, the frequency of haplotype T-b-C was higher in late sPE vs early sPE and normotensive pregnant. Considering the results found for eNOS polymorphisms, it is possible to suggest that the functional alterations induced by these two polymorphisms may influence the time of severe PE onset, although both alterations are putatively associated with low NO bioavailability. However, other studies are necessary to validate these findings and clarify this issue. | 25,106,888 | [
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Dynamic fabrication of tissue-engineered bone substitutes based on derived cancellous bone scaffold in a spinner flask bioreactor system. | The in vitro dynamic fabrications of tissue-engineered bones were performed to assess the advantages of human adipose-derived stem cells (hADSCs) combined with acellular cancellous bone scaffold coming from fresh pig femur in a spinner flask compared with traditional static culture. In this study, the bio-derived cancellous bone was regarded as a biomimetic scaffold, and its surface appearance was observed under scanning electron microscopy (SEM). Moreover, its modulus of elasticity and chemical composition were measured with universal testing machine (UTM) and infrared detector, respectively. hADSCs were inoculated into cancellous bone scaffold at a density of 1 × 10(6) cells/mL and cultured in spinner flask and T-flask with osteogenic medium (OM) for 2 weeks, respectively. Following to this, the osteogenic differentiation was qualitatively and quantitatively detected with alkaline phosphatase (ALP) kits, and the cell growth and viability were assayed using Live/Dead staining; cell adhesion and extracellular matrix secretion were observed under a SEM. The average pore size of cancellous bone scaffold was 284.5 ± 83.62 μm, the elasticity modulus was 41.27 ± 15.63 MPa, and it also showed excellent biocompatibility. The hADSCs with multidifferentiation potentials were well proliferated, could grow to 90 % fusion within 5 days, and were therefore suitable to use as seed cells in the construction of tissue-engineered bones. After 2 weeks of fabrication, cells were well-distributed on scaffolds, and these scaffolds still remained intact. Compared to static environment, the ALP expression, cell distribution, and extracellular matrix secretion on cancellous bones in spinner flask were much better. It confirmed that three-dimensional dynamic culture in spinner flask promoted ADSC osteogenic differentiation, proliferation, and matrix secretion significantly to make for the fabrication of engineered bone substitutes. | 25,106,897 | [
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CPP-mediated protein delivery in a noncovalent form: proof-of-concept for percutaneous and intranasal delivery. | Macromolecular drugs (e.g., proteins and nucleic acids) are highly environmentally liable and unstable, and their administration is strictly limited to injection. Moreover, a vast majority of macromolecules are cell membrane- impermeable, and it is a critical issue to enhance the cellular uptake efficiency for improving the treatment outcomes. Cell-penetrating peptide (CPP)-assisted strategy is promising for effective macromolecular delivery. As a case in point, CPP-mediated protein delivery has been considered as a revolutionary breakthrough. With aid of CPP, virtually all pro- teins can become cell-permeable. Generally, CPP-protein delivery works in a covalent delivery pattern, by which CPP and its cargo are linked via covalent bond. Recently, noncovalent delivery has also attracted attention for its potential application for protein delivery. In the presented work, the noncovalent pattern was demonstrated for its feasibi lity in percutaneous and nose-to-brain delivery with TAT/GFP as model drug, in comparison with the covalent method. Noncovalent CPP/protein delivery and its noninvasive application may provide a facile method for protein therapy. | 25,106,905 | [
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Desertibacter xinjiangensis sp. nov., isolated from the soil of a Euphrates poplar forest, and emended description of the genus Desertibacter. | A pale pink and strictly aerobic bacterium, designated strain M71(T), was isolated from the soil of a Euphrates poplar forest in Xingjiang, PR China. Cells of the strain were Gram-reaction-negative, rod-shaped and motile by means of a single polar flagellum. Growth occurred at 10-37 °C (optimum 30 °C), at pH 6.0-9.0 (optimum pH 7.0-8.0) and with 0-2.0% NaCl (w/v, optimum 0%). Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that strain M71(T) belongs to the genus Desertibacter in the family Rhodospirillaceae. The 16S rRNA gene sequence of this strain showed 96.2% sequence similarity with the type strain of Desertibacter roseus 2262(T). The respiratory quinone was Q-10 and the predominant cellular fatty acids were C(18:1)ω7c (53.2%), C(16:1)ω5c (11.0%), summed feature 3 (C(16:1)ω7c and/or C(16:1)ω6c, 10.2%) and C(16:0) (8.5%). The DNA G+C content was 71.2 mol% (HPLC). The strain contained phosphatidylcholine and phosphatidylethanolamine as the predominant polar lipids. On the basis of the phenotypic, chemotaxonomic and phylogenetic data, strain M71(T) is considered to represent a novel species of the genus Desertibacter, for which the name Desertibacter xinjiangensis sp. nov. is proposed. The type strain is M71(T) ( =CCTCC AB 209291(T) =CIP 110127(T)). | 25,106,921 | [
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De-identification of clinical narratives through writing complexity measures. | Electronic health records contain a substantial quantity of clinical narrative, which is increasingly reused for research purposes. To share data on a large scale and respect privacy, it is critical to remove patient identifiers. De-identification tools based on machine learning have been proposed; however, model training is usually based on either a random group of documents or a pre-existing document type designation (e.g., discharge summary). This work investigates if inherent features, such as the writing complexity, can identify document subsets to enhance de-identification performance. We applied an unsupervised clustering method to group two corpora based on writing complexity measures: a collection of over 4500 documents of varying document types (e.g., discharge summaries, history and physical reports, and radiology reports) from Vanderbilt University Medical Center (VUMC) and the publicly available i2b2 corpus of 889 discharge summaries. We compare the performance (via recall, precision, and F-measure) of de-identification models trained on such clusters with models trained on documents grouped randomly or VUMC document type. For the Vanderbilt dataset, it was observed that training and testing de-identification models on the same stylometric cluster (with the average F-measure of 0.917) tended to outperform models based on clusters of random documents (with an average F-measure of 0.881). It was further observed that increasing the size of a training subset sampled from a specific cluster could yield improved results (e.g., for subsets from a certain stylometric cluster, the F-measure raised from 0.743 to 0.841 when training size increased from 10 to 50 documents, and the F-measure reached 0.901 when the size of the training subset reached 200 documents). For the i2b2 dataset, training and testing on the same clusters based on complexity measures (average F-score 0.966) did not significantly surpass randomly selected clusters (average F-score 0.965). Our findings illustrate that, in environments consisting of a variety of clinical documentation, de-identification models trained on writing complexity measures are better than models trained on random groups and, in many instances, document types. | 25,106,934 | [
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Association of common SNP rs1136410 in PARP1 gene with the susceptibility to male infertility with oligospermia. | This study aims to explore possible associations between polymorphisms of common SNP rs1136410 and rS1805405 in PARP1 gene and male infertility with spermatogenesis impairment. The polymorphic distributions of SNP rs1136410 and rS1805405 were investigated by polymerase chain reaction and restriction fragment length polymorphism analysis in a Chinese cohort including 371 infertile patients with idiopathic azoospermia or oligospermia and 231 controls. Significant differences in the frequencies of allele and genotype of SNP rs1136410 were observed between patients with oligospermia and controls. The allele C (46.3 % vs. 36.4 %, P = 0.003) and genotype CC (22.6 % vs. 13.4 %, P = 0.014) significantly increased, whereas genotype TT (30 % vs. 40.7 %, P = 0.021) significantly decreased in patients with oligospermia compared with controls at this SNP locus. These results indicated that genotype CC of SNP rs1136410 may increase the risk of oligosoermia and genotype TT of rs1136410 may have some protective effect from oligospermia, suggesting that the polymorphism of SNP rs1136410 in PARP1 gene may modify the susceptibility to male infertility with oligospermia. | 25,106,941 | [
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Subspecialty emergency room as alternative model for otolaryngologic care: implications for emergency health care delivery. | A dedicated otolaryngology emergency room (ER) represents a specialized surgical evaluation and treatment setting that may be an alternative triage pathway for acute otolaryngologic complaints. We aim to characterize practice patterns in this setting and to provide insight into the epidemiology of all-comer, urgent otolaryngologic complaints in the United States. Electronic medical records were reviewed for all patients who registered for otolaryngologic care and received a diagnosis in the Massachusetts Eye and Ear Infirmary ER between January 2011 and September 2013. Descriptive analysis was performed to characterize utilization and diagnostic patterns. Predictors of inpatient admission were identified using multivariable regression. Geocoding analysis was performed to characterize catchment area. A total of 12,234 patient visits were evaluated with a mean age of 44.7. Auditory and vestibular problems constituted the most frequent diagnoses (50.0%). The majority of patients were discharged home (92.3%). Forty-three percent of patients underwent a procedure in the ER; the most common procedure was diagnostic nasolaryngoscopy (52%). Predictors of inpatient admission were post-operative complaint (odds ratio [OR] 7.3, P<0.0001), arrival overnight (OR 3.3, P<0.0001), and laryngeal complaint (OR 2.4, P<0.0001). Patients traveled farther for evaluation of hearing loss (11 miles) and less for common diagnoses including impacted cerumen (7.1 miles) (P<0.0001). In this report, we investigate practice patterns of a dedicated otolaryngology emergency room to explore an alternative to standard acute otolaryngologic health care delivery mechanisms. We identify key predictors of inpatient admission. This study has implications for emergency health care delivery models. | 25,106,951 | [
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Stability, complexity and robustness in population dynamics. | The problem of stability in population dynamics concerns many domains of application in demography, biology, mechanics and mathematics. The problem is highly generic and independent of the population considered (human, animals, molecules,…). We give in this paper some examples of population dynamics concerning nucleic acids interacting through direct nucleic binding with small or cyclic RNAs acting on mRNAs or tRNAs as translation factors or through protein complexes expressed by genes and linked to DNA as transcription factors. The networks made of these interactions between nucleic acids (considered respectively as edges and nodes of their interaction graph) are complex, but exhibit simple emergent asymptotic behaviours, when time tends to infinity, called attractors. We show that the quantity called attractor entropy plays a crucial role in the study of the stability and robustness of such genetic networks. | 25,107,273 | [
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Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics. | Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH. | 25,107,291 | [
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The mechanism of enterohepatic circulation in the formation of gallstone disease. | Bile acids entering into enterohepatic circulating are primary acids synthesized from cholesterol in hepatocyte. They are secreted actively across canalicular membrane and carried in bile to gallbladder, where they are concentrated during digestion. About 95% BAs are actively taken up from the lumen of terminal ileum efficiently, leaving only approximately 5% (or approximately 0.5 g/d) in colon, and a fraction of bile acids are passively reabsorbed after a series of modifications in the human large intestine including deconjugation and oxidation of hydroxy groups. Bile salts hydrolysis and hydroxy group dehydrogenation reactions are performed by a broad spectrum of intestinal anaerobic bacteria. Next, hepatocyte reabsorbs bile acids from sinusoidal blood, which are carried to liver through portal vein via a series of transporters. Bile acids (BAs) transporters are critical for maintenance of the enterohepatic BAs circulation, where BAs exert their multiple physiological functions including stimulation of bile flow, intestinal absorption of lipophilic nutrients, solubilization, and excretion of cholesterol. Tight regulation of BA transporters via nuclear receptors (NRs) is necessary to maintain proper BA homeostasis. In conclusion, disturbances of enterohepatic circulation may account for pathogenesis of gallstones diseases, including BAs transporters and their regulatory NRs and the metabolism of intestinal bacterias, etc. | 25,107,305 | [
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Two C4-sterol methyl oxidases (Erg25) catalyse ergosterol intermediate demethylation and impact environmental stress adaptation in Aspergillus fumigatus. | The human pathogen Aspergillus fumigatus adapts to stress encountered in the mammalian host as part of its ability to cause disease. The transcription factor SrbA plays a significant role in this process by regulating genes involved in hypoxia and low-iron adaptation, antifungal drug responses and virulence. SrbA is a direct transcriptional regulator of genes encoding key enzymes in the ergosterol biosynthesis pathway, including erg25A and erg25B, and ΔsrbA accumulates C4-methyl sterols, suggesting a loss of Erg25 activity [C4-sterol methyl oxidase (SMO)]. Characterization of the two genes encoding SMOs in Aspergillus fumigatus revealed that both serve as functional C4-demethylases, with Erg25A serving in a primary role, as Δerg25A accumulates more C4-methyl sterol intermediates than Δerg25B. Single deletion of these SMOs revealed alterations in canonical ergosterol biosynthesis, indicating that ergosterol may be produced in an alternative fashion in the absence of SMO activity. A Δerg25A strain displayed moderate susceptibility to hypoxia and the endoplasmic reticulum stress-inducing agent DTT, but was not required for virulence in murine or insect models of invasive aspergillosis. Inducing expression of erg25A partially restored the hypoxia growth defect of ΔsrbA. These findings implicated Aspergillus fumigatus SMOs in the maintenance of canonical ergosterol biosynthesis and indicated an overall involvement in the fungal stress response. | 25,107,308 | [
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C-reactive protein and risk of fracture: a systematic review and dose-response meta-analysis of prospective cohort studies. | This study systematically reviews prospective cohort studies evaluating the relationship between C-reactive protein (CRP) concentrations and subsequent fracture risk. The positive association cannot completely explain the existing evidence, and further studies are needed to demonstrate the shape of the association. We aimed to perform a systematic review and dose-response meta-analysis of published prospective studies evaluating associations of high-sensitivity CRP (hs-CRP) levels with fracture risk in general populations. We identified relevant studies by searching MEDLINE and EMBASE databases from their inception to May 20, 2014. We included published prospective studies evaluating the associations of hs-CRP levels with risk of fracture in general populations. Two reviewers working independently abstracted the data. Eight prospective cohort studies involving 34,840 participants and 3,407 incident fracture events were eligible for the present analyses. A meta-analysis of six prospective studies showed that the overall risk for incident fracture in a comparison of individuals in the top tertile with those in the bottom tertile of baseline hs-CRP levels was 2.14 [95% confidence interval (CI) 1.51-3.05, I(2) = 62.3%]. The moderate heterogeneous disappeared when one study was excluded. However, the remaining two studies reported inconsistent results. One study with the biggest sample size showed a U-shaped association for CRP and fracture risk (the association was positive when CRP > 1 mg/L). Similarly, another study reported that per doubling of CRP was positive only when CRP > 3 mg/L. In summary, the present analysis showed that the relationship between CRP concentrations and subsequent fracture risk is still inconsistent. The positive association cannot completely explain the existing evidence, and further larger prospective cohorts with more power are needed to demonstrate the shape of the association, especially for the relatively low CRP concentrations, such as less than 3 mg/L. | 25,107,320 | [
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Mechanical work and energy consumption in children with cerebral palsy after single-event multilevel surgery. | Multilevel surgery is commonly performed to improve walking in children with cerebral palsy (CP). Classical gait analysis (kinetics, kinematics) demonstrated positive outcomes after this intervention, however it doesn't give global indication about gait's features. The assessment of energy cost and mechanical work of locomotion can provide an overall description of walking functionality. Therefore, we propose to describe the effects of multilevel surgery in children with CP, considering energetics, mechanical work, kinetic and kinematic of walking. We measured external, internal, total work, energy cost, recovery, efficiency, kinetic and kinematic of walking in 10 children with CP (4 girls, 6 boys; 13 years ± 2) before and 1 year after multilevel surgery. Kinetic and kinematic results are partially comparable to previous findings, energy cost of walking is significantly reduced (p < 0.05); external, internal, total work, recovery, efficiency are not significantly different (p = 0.129; p = 0.147; p = 0.795; p = 0.119; p = 0.21). The improvement of the walking's energy consumption is not accompanied by a corresponding improvement of mechanical work. Therefore it is conceivable that the improvement of walking economy depend on a reduced effort of the muscle to maintain the posture, rather then to an improvement of the mechanism of energy recovery typical of human locomotion. | 25,107,323 | [
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[Maternal and perinatal outcomes in nulliparous gestations with late onset preeclampsia: Comparative study with gestations without preeclampsia]. | To assess obstetrical outcomes in a sample of nulliparous gestations with preeclampsia, as compared to gestations without preeclampsia, attended in the Enrique C. Sotomayor Hospital of Guayaquil, Ecuador. This was a comparative study of maternal and perinatal outcome data of gestations with late onset preeclampsia (n=150; gestational age=36.7±3.3 weeks) with that of normal gestations (n=150; gestational age 38.7±1.7 weeks). Almost three-quarters (73.3%) of preeclampsia cases were defined as severe. Compared to normal gestations, preeclampsia cases had higher anthropometric indices (neck and mid-arm circumference) and had more oligohydramnios, cesarean sections, transfusions, distressed fetuses, and adverse perinatal outcomes such as, lower Apgar scores at birth, and more preterm births, lower birth weight and small for gestational age infants. Gestations with preeclampsia had a negative impact on maternal and perinatal outcomes compared to gestations without preeclampsia. | 25,107,334 | [
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Characteristics and outcomes of patients with multiple myeloma who develop therapy-related myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia. | Patients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients. Patients with MM treated at our institution from 1993 to 2011 were reviewed. Forty-seven patients were diagnosed with t-MN. Our primary objective was to evaluate the interval to t-MN, response to treatment, and overall survival (OS). The median patient age at the MM diagnosis was 65 years. Of the 47 patients, 32 (68.0%) initially received conventional chemotherapeutic agents, 7 (14.9%), novel agents (eg, lenalidomide, thalidomide, bortezomib), and 8 (17.0%), a combination. Twenty patients (42.6%) underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The median interval from the MM diagnosis to t-MN was 7 years (95% CI, 5.0-28.0). Of the 47 patients, 33 (70.2%) developed therapy-related myelodysplastic syndrome (t-MDS), 11 (23.4%) acute myeloid leukemia (t-AML), and 3 (6.4%) chronic myelomonocytic leukemia (t-CMML). The median age at the t-MN diagnosis was 65 years. Of the 47 patients, 26 (78.8%) with t-MDS, 9 (81.8%) with t-AML, and 1 (33.3%) with t-CMML had complex/high-risk cytogenetics. The median OS for all 47 patients after the t-MN diagnosis was 6.3 months (95% CI, 4.0-8.7). The development of t-MN in patients with MM is associated with poor outcomes. These patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times. A better understanding of the disease biology and novel therapeutic approaches are warranted. | 25,107,338 | [
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Use of multiplex PCR in diagnosis of bloodstream infections in kidney patients. | The LightCycler® SeptiFast Test (Roche Diagnostics GmbH, Mannheim, Germany) was prospectively compared with the standard blood culture technique in a series of 86 kidney patients. The sensitivity of the PCR compared with the culture was 71%, and the specificity was 88%. All the species identified by culture in these patients were in the SeptiFast panel. The median time to results was 1 day for the PCR, 3 days for positive cultures, and 5 days for negative cultures. | 25,107,361 | [
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CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway. | Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1-ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ-binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr(-/-) and cftr(ΔF508) mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis. | 25,107,366 | [
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Secreted fibroblast-derived miR-34a induces tubular cell apoptosis in fibrotic kidney. | Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remains unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrate that miR-34a is markedly upregulated in tubulointerstitial spaces and microvesicles isolated from obstructed kidney. However, miR-34a is not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubation with TGF-β1. miR-34a is markedly upregulated in microvesicles isolated from the cell culture medium of TGF-β1-treated fibroblasts. These microvesicles act as a vector for delivery of upregulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induce the apoptosis of tubular cells. The exogenous miR-34a regulates tubular apoptosis by modulating the expression of the anti-apoptotic protein Bcl-2. Moreover, injection of exogenous miR-34a-containing microvesicles enhances tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructed kidney. This study reveals a new mechanism whereby microvesicle-mediated communication of miRNA between fibroblasts and tubular cells is involved in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis. | 25,107,369 | [
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Natural products for the management of type 2 diabetes mellitus and comorbid conditions. | To provide pharmacists with practical information to guide consumers in their choices of herbal products and dietary supplements for the management of type 2 diabetes mellitus (T2DM) and its comorbid disease states. The herbal and dietary supplement market has grown exponentially over the past decade as Americans increasingly use such agents for generalized health and the prevention and treatment of chronic disease states.1 Pharmacist advice is often requested on the use of these agents for the management of T2DM; however, this is an area that has insufficient evidence to support confident recommendations. Many published studies involving herbal agents and dietary supplements are small and poorly designed, with heterogeneous results. Pharmacists should be aware of the safety and efficacy data available for these agents, recognize potential drug interactions, and identify acceptable manufactured products. The strongest scientific evidence for blood glucose lowering effect is associated with alpha-lipoic acid and fenugreek. There is also good evidence supporting the use of ivy gourd, gymnema, and vitamin E for management of hyperglycemia; however, caution should be used when recommending vitamin E. Pharmacists should advise consumers to disclose use of any of these products to all of their health care providers. | 25,107,389 | [
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Children's effortful control and academic achievement: do relational peer victimization and classroom participation operate as mediators? | Given that early academic achievement is related to numerous developmental outcomes, understanding processes that promote early success in school is important. This study was designed to clarify how students' (N=291; M age in fall of kindergarten=5.66 years, SD=0.39 year) effortful control, relational peer victimization, and classroom participation relate to achievement, as students progress from kindergarten to first grade. Effortful control and achievement were assessed in kindergarten, classroom participation and relational peer victimization were assessed in the fall of first grade, and achievement was reassessed in the spring of first grade. Classroom participation, but not relational peer victimization, mediated relations between effortful control and first grade standardized and teacher-rated achievement, controlling for kindergarten achievement. Findings suggest that aspects of classroom participation, such as the ability to work independently, may be useful targets of intervention for enhancing academic achievement in young children. | 25,107,413 | [
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A review of paroxetine for the treatment of vasomotor symptoms. | Studies in recent years have exposed concerns about the safety of hormone replacement therapy (HRT) in the treatment of vasomotor symptoms (VMS) in menopausal women. Numerous studies have examined the use of antidepressants for relief of VMS. Despite recommendations to deny approval of paroxetine mesylate (Brisdelle™) for the treatment of VMS, the Food and Drug Administration (FDA) recently granted it approval for this indication. To evaluate all published literature examining use of paroxetine salts (mesylate and hydrochloride) in the treatment of menopausal VMS. Both PubMed and International Pharmaceutical Abstracts (IPA) were searched using the keywords hot flashes, vasomotor symptoms, menopause, and paroxetine. In PubMed, MeSH terms were used for paroxetine, menopause, and hot flashes. Searches were limited to humans, English language, and clinical trial design. The references for each study identified in this search process were examined in order to locate any additional relevant articles. Compared with placebo, paroxetine salts offer a modest benefit in the treatment of menopausal VMS reducing the frequency and severity of weekly hot flashes. Paroxetine (mesylate or hydrochloride) is an effective alternative to HRT for the reduction in VMS in menopausal women. Future head-to-head studies with active medications are needed in order to identify the best algorithm of treatment for this condition. | 25,107,421 | [
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Intrapleural Antimicrobial Irrigation for Postpneumonectomy Empyema in Patients With Lung Cancer. | Postpneumonectomy empyema (PPE) is a possible complication after a pneumonectomy in patients with lung cancer. The use of intrapleural (IP) antibiotic irrigation to treat infections in the pleural space may be indicated after systemic antimicrobial therapy, and drainage of the pleural space has been insufficient. Adult patients ≥18 years old who received IP antibiotic irrigation between 2006 and 2011 were included. Demographic data, past medical history, surgical procedure, systemic antibiotics, and culture data were collected. Additionally, the IP antibiotic administered, the dose, and how it was prepared and administered were collected. A total of 18 patients were evaluated in this retrospective descriptive analysis. The majority of patients underwent an extrapleural pneumonectomy (EPP; 72%). Most patients received systemic antibiotics before IP antibiotic administration (95%). Vancomycin was the most common antibiotic used for both systemic therapy (100%) and IP irrigation (94%). The median number of IP antibiotic doses received per patient was 5.5 (interquartile range [IQR] 1-9). Recurrence of PPE within 6 months of initial PPE resolution occurred in 28% of patients. Intrapleural antibiotic irrigation was well tolerated in all patients. Vancomycin is most commonly used for IP antibiotic irrigation at our institution after patients have undergone a thoracic surgery, which was most commonly an EPP. | 25,107,425 | [
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Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA. | Despite the growing number of point-of-care (POC) tests available, little research has assessed primary care clinician need for such tests. We therefore aimed to determine which POC tests they actually use or would like to use (if not currently available in their practice). Cross-sectional survey. Primary care in Australia, Belgium (Flanders region only), the Netherlands, the UK and the USA. Primary care doctors (general practitioners, family physicians). We asked respondents to (1) identify conditions for which a POC test could help inform diagnosis, (2) from a list of tests provided: evaluate which POC tests they currently use (and how frequently) and (3) determine which tests (from that same list) they would like to use in the future (and how frequently). 2770 primary care clinicians across five countries responded. Respondents in all countries wanted POC tests to help them diagnose acute conditions (infections, acute cardiac disease, pulmonary embolism/deep vein thrombosis), and some chronic conditions (diabetes, anaemia). Based on the list of POC tests provided, the most common tests currently used were: urine pregnancy, urine leucocytes or nitrite and blood glucose. The most commonly reported tests respondents expressed a wish to use in the future were: D-dimer, troponin and chlamydia. The UK and the USA reported a higher actual and desired use for POC tests than Australia, Belgium and the Netherlands. Our limited data suggest (but do not confirm) representativeness. Primary care clinicians in all five countries expressed a desire for POC tests to help them diagnose a range of acute and chronic conditions. Rates of current reported use and desired future use were generally high for a small selection of POC tests, but varied across countries. Future research is warranted to explore how specific POC tests might improve primary care. | 25,107,438 | [
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Phospholipid transfer protein in diabetes, metabolic syndrome and obesity. | It has been reported that phospholipid transfer protein (PLTP) is an independent risk factor for human coronary artery disease. And metabolic tissues are important contributors to the systemic pools of PLTP protein. Consistently, PLTP mass and activity have been found to be elevated in the plasma of type 2 diabetes mellitus (T2DM) and obese patients. In this review, we summarized the recent progresses made in the PLTP research field and focused on the complexity of the implication of PLTP in obesity, insulin resistance and T2DM. | 25,107,452 | [
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HepaRG microencapsulated spheroids in DMSO-free culture: novel culturing approaches for enhanced xenobiotic and biosynthetic metabolism. | The need for models that recapitulate liver physiology is perceived for drug development, study of liver disease and bioartificial liver support. The bipotent cell line HepaRG constitutes an efficient surrogate of liver function, yet its differentiated status relies on high concentrations of DMSO, which may compromise the study of drug metabolism and limit the applicability of this hepatic model. Herein, we present a three-dimensional (3D) strategy for the differentiation of HepaRG based on alginate microencapsulation of cell spheroids and culture in dimethyl sulfoxide (DMSO)-free conditions. A ratio of 2.9:1 hepatocyte-like to biliary-like cells was obtained in the 3D culture, with an improvement of 35.9 % in the hepatocyte differentiation when compared with two-dimensional (2D) cultures. The expression of the hepatic identity genes HNF4α and PXR in 3D cultures was comparable to 2D differentiated cultures, while the expression of homeostatic-associated genes albumin and carbamoyl phosphate synthase 1 was higher in 3D. Moreover, the spheroids presented a polarized organization, exhibiting an interconnected bile canalicular network and excretory functionality, assessed by specific activity of MRP2. Importantly, despite variability in basal gene expression levels, the activity of the phase I enzymes cytochrome P450 family 3, subfamily A, polypeptide 4 and cytochrome P450 family 1, subfamily A, polypeptide 2 upon induction was comparable to differentiated 2D cultures and albumin production and ammonia detoxification were enhanced in 3D. The presented model is suitable for toxicological applications, as it allows high throughput analysis of multiple compounds in a DMSO-free setting. Due to the high xenobiotic metabolism and maintenance of biosynthetic functions, the applicability of this model might be broadened to understand liver physiology and for bioartificial liver applications. | 25,107,451 | [
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Far lateral paracondylar versus transcondylar approach in the pediatric age group: CT morphometric analysis. | This study aimed to determine if partial removal of the occipital condyle provides a significant increase in visibility and "angle of attack" for treating lesions with extension ventral to the brainstem in children using CT morphometric data. Morphometric analysis was performed in 199 children using CT scans. Angle of attack was measured for both the paracondylar and transcondylar far lateral approach. Statistical analysis was performed using paired or unpaired Student's t-tests (p<0.05) and linear regression analysis. For the far lateral paracondylar approach, the overall angle of attack was 85 ± 9 degrees (range, 60-119 degrees). The overall angle of attack for the far lateral transcondylar approach was 70 ± 9 degrees (range, 48-105 degrees). This difference was significant (p<0.0001). Based on our data, resection of one-third of the occipital condyle in a far lateral transcondylar approach can improve angle of attack by approximately 15 degrees, regardless of age or sex, in the pediatric age group. It is important to keep in mind that there are risks attendant to resection of the occipital condyle, thus the resection of the occipital condyle in children should not be a mandatory part of the far lateral approach; rather, the decision-making should be individualized and considered on a case-by-case basis. | 25,107,454 | [
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Incidence and morbidity of craniocervical arterial dissections in atraumatic subarachnoid hemorrhage patients who underwent aneurysmal repair. | No studies have assessed the incidence of craniocervical arterial dissections (CCADs) and its association to mortality in hospitalized patients with a primary diagnosis of atraumatic subarachnoid hemorrhage (SAH) requiring aneurysmal repair. We hypothesize that the incidence of CCADs in these patients has increased over time as well as its association to mortality. We conducted a 9 year retrospective assessment of the incidence of CCADs in patients hospitalized with a primary diagnosis of an SAH requiring repair and the effect of CCAD on mortality. Using the Nationwide Inpatient Sample (NIS), we queried records from 2003 to 2011 for an ICD-9 (International Classification of Diseases-9) code corresponding to admissions for atraumatic SAH. Demographical data, incidence of CCADs, type of aneurysmal repair, length of hospital stay, and hospital mortality were recorded. Multivariate logistical regression models were fitted to assess for the impact of CCAD on inhospital mortality and morbidity. During the period 2003-2011, of the NIS reported 18,260 patients who required aneurysmal SAH repair, 9737 (53.32%) underwent endovascular coiling and 8523 (46.48%) had surgical clipping. There were 131 patients in the cohort with reported CCADs: 94 (71.75%) of these patients had received endovascular coiling repair and 37 (28.25%) had undergone surgical clipping repair. Patients who underwent endovascular coiling had a higher rate of CCADs in this cohort (OR 2.94; 95% CI 2.00 to 4.31, p<0.0001). The incidence of CCADs in this population increased by an average rate of 9.4% per year (OR 1.14; 95% CI 1.06 to 1.23, p<0.0006), from 0.49% in 2003 to 1.10% in 2011. The diagnosis of CCAD added 3 and 6 more days to median length of hospitalization stay for surgical clipping and endovascular coiling, respectively. The unadjusted rate of mortality was 8.4% in the CCADs subgroup, and the presence of CCAD was not a predictor of mortality in our multivariate regression model (OR 0.68; 95% CI 0.36 to 1.27, p=0.2244). Our study indicates an annual increase in the incidence of CCADs in patients admitted with SAH who require aneurysmal repair. More than two-thirds of these patients that developed CCADs had undergone endovascular coiling repair. A diagnosis of CCAD increased the length of hospital stay but had no statistically significant association with mortality in this patient population. | 25,107,470 | [
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Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex. | Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. | 25,107,474 | [
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A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. | The last decade has been marked by tremendous progress in our understanding of the cell biology of mitochondria, with the identification of molecules and mechanisms that regulate their fusion, fission, motility, and the architectural transitions within the inner membrane. More importantly, the manipulation of these machineries in tissues has provided links between mitochondrial dynamics and physiology. Indeed, just as the proteins required for fusion and fission were identified, they were quickly linked to both rare and common human diseases. This highlighted the critical importance of this emerging field to medicine, with new hopes of finding drugable targets for numerous pathologies, from neurodegenerative diseases to inflammation and cancer. In the midst of these exciting new discoveries, an unexpected new aspect of mitochondrial cell biology has been uncovered; the generation of small vesicular carriers that transport mitochondrial proteins and lipids to other intracellular organelles. These mitochondrial-derived vesicles (MDVs) were first found to transport a mitochondrial outer membrane protein MAPL to a subpopulation of peroxisomes. However, other MDVs did not target peroxisomes and instead fused with the late endosome, or multivesicular body. The Parkinson's disease-associated proteins Vps35, Parkin, and PINK1 are involved in the biogenesis of a subset of these MDVs, linking this novel trafficking pathway to human disease. In this review, we outline what has been learned about the mechanisms and functional importance of MDV transport and speculate on the greater impact of these pathways in cellular physiology. | 25,107,473 | [
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Glycemic control among U.S. Hispanics/Latinos with diabetes from the HCHS/SOL Sociocultural Ancillary Study: do structural and functional social support play a role? | Social support is one potential source of health-related resiliency in Hispanics with diabetes. This study examined relationships of structural (i.e., social integration) and functional (i.e., perceived) social support with glycemic control (glycosylated hemoglobin; HbA1c) in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. This study included 766 men and women representing multiple Hispanic ethnic backgrounds, aged 18-74 years, with diagnosed diabetes who completed fasting blood draw, medication review, and measures of sociodemographic factors, medical history, structural support (Cohen Social Network Index), and functional support (Interpersonal Support Evaluation List-12). After adjusting for sociodemographic covariates and medication, a one standard deviation increase in functional support was related to an 0.18% higher HbA1c (p = 0.04). A similar trend was observed for structural support; however, this effect was non-significant in adjusted models. Greater functional support was associated with poorer glycemic control in Hispanics. | 25,107,503 | [
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Testing manifest monotonicity using order-constrained statistical inference. | Most dichotomous item response models share the assumption of latent monotonicity, which states that the probability of a positive response to an item is a nondecreasing function of a latent variable intended to be measured. Latent monotonicity cannot be evaluated directly, but it implies manifest monotonicity across a variety of observed scores, such as the restscore, a single item score, and in some cases the total score. In this study, we show that manifest monotonicity can be tested by means of the order-constrained statistical inference framework. We propose a procedure that uses this framework to determine whether manifest monotonicity should be rejected for specific items. This approach provides a likelihood ratio test for which the p-value can be approximated through simulation. A simulation study is presented that evaluates the Type I error rate and power of the test, and the procedure is applied to empirical data. | 25,107,519 | [
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Optimal and most exact confidence intervals for person parameters in item response theory models. | The common way to calculate confidence intervals for item response theory models is to assume that the standardized maximum likelihood estimator for the person parameter θ is normally distributed. However, this approximation is often inadequate for short and medium test lengths. As a result, the coverage probabilities fall below the given level of significance in many cases; and, therefore, the corresponding intervals are no longer confidence intervals in terms of the actual definition. In the present work, confidence intervals are defined more precisely by utilizing the relationship between confidence intervals and hypothesis testing. Two approaches to confidence interval construction are explored that are optimal with respect to criteria of smallness and consistency with the standard approach. | 25,107,520 | [
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Surface texture and priming play important roles in predator recognition by the red-backed shrike in field experiments. | We compared the responses of the nesting red-backed shrikes (Lanius collurio) to three dummies of a common nest predator, the Eurasian jay (Garrulus glandarius), each made from a different material (stuffed, plush, and silicone). The shrikes performed defensive behaviour including attacks on all three dummies. Nevertheless, the number of attacks significantly decreased from the stuffed dummy through the plush dummy and finally to the silicone dummy. Our results show that wild birds use not only colours but also other surface features as important cues for recognition and categorization of other bird species. Moreover, the silicone dummy was attacked only when presented after the stuffed or plush dummy. Thus, we concluded that the shrikes recognized the jay only the stuffed (with feathered surface) and plush (with hairy surface) dummies during the first encounter. Recognition of the silicon dummy (with glossy surface) was facilitated by previous encounters with the more accurate model. This process resembles the effect of perceptual priming, which is widely described in the literature on humans. | 25,107,529 | [
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MAGE proteins regulate KRAB zinc finger transcription factors and KAP1 E3 ligase activity. | Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved. | 25,107,531 | [
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The role of CXC chemokine receptor 2 in Staphylococcus aureus keratitis. | Staphylococcus aureus is a leading cause of corneal infection. CXC receptor 2 binding chemokines have been implicated in the pathogenesis of Pseudomonas aeruginosa keratitis. The role of this receptor in immune responses during Staphylococcus keratitis remains to be fully understood. Corneas of CXC receptor 2 knockout and wild-type mice (Cmkar -/- & Cmkar +/+) were scratched and 1 × 10(8) cfu/ml of strain Staph 38 applied. Twenty-four hours post-infection, mice were sacrificed and eyes harvested for enumeration of bacteria and measurement of myeloperoxidase levels. Production of inflammatory mediators, cellular adhesion molecules and chemokines in response to infection were investigated by ELISA, and PCR. 24 h after challenge with S. aureus, Cmkar -/- mice had developed a more severe response with a 50-fold higher bacterial load than WT mice. PMNs failed to penetrate the corneas of Cmkar -/- mice. However, concentrations of KC, MIP-2, IL-1β and IL-6 were significantly elevated (6-13 fold) in Cmkar-/- mice. The concentration of LTB4 was decreased (2 fold). Cmkar-/- mice failed to upregulate mRNA for VCAM-1 or PECAM-1 in response to infection, but had constitutively higher levels of ICAM-1. A lack of CXC receptor 2 lead to an inability to control bacterial numbers as a result of failure of PMNs to penetrate the cornea to the site of infection, even when chemokines were more highly produced. These results imply that CXCR2-mediated signaling through upregulation of adhesion molecules is essential to margination of PMNs in this infection model. | 25,107,538 | [
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Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. | In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis. Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway. Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis. Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling. | 25,107,557 | [
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The rescuable function and mechanism of resveratrol on As₂O₃-induced hERG K⁺ channel deficiency. | Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity. | 25,107,562 | [
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Phase II gemcitabine and capecitabine combination therapy in recurrent or metastatic breast cancer patients pretreated with anthracycline and taxane. | We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea. This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m(2) gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m(2) capecitabine orally twice daily on days 1-14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen. Of 41 patients, the ORR was 39.0% (CR 0%; PR 39.0%), and DCR was 78.0% using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8%, respectively. Median PFS was 10.0 months [95% confidence interval (CI) 7.8-12.1], and median OS was 25.1 months (95% CI 18.2-32.1). Prominent toxicities were neutropenia and hand-foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95% CI 0.034-0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95% CI 0.017-0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination. This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane. | 25,107,569 | [
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Anticancer activity of VDR-coregulator inhibitor PS121912. | PS121912 has been developed as selective vitamin D receptor (VDR)-coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule. Antiproliferation and apoptosis were determined using four different cancer cell lines (DU145, Caco2, HL-60 and SKOV3) in the presence of PS121912, 1,25-(OH)₂D₃, or a combination of 1,25-(OH)₂D₃ and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by RT-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 includes the determination of metabolic stability and CYP3A4 inhibition. PS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)₂D₃ without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)₂D₃ were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)₂D₃ reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factors 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)₂D₃ that in turn reduced the transcription levels of cyclin A and D, thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopoietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1, also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)₂D₃ and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7. Overall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies. | 25,107,568 | [
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Family history as a risk factor for peripheral arterial disease. | The association of a family history of peripheral arterial disease (PAD) with the presence of PAD is largely unknown. We conducted a case-control study of 2,296 patients with PAD (69 ± 10 years, 64% men) and 4,390 controls (66 ± 11 years, 62% men) identified from noninvasive vascular and stress testing laboratories at Mayo Clinic, Rochester, Minnesota, from October 2006 through June 2012. PAD was defined as an ankle brachial index of ≤ 0.9 at rest and/or after exercise, a history of lower extremity revascularization, or having poorly compressible leg arteries. Controls were patients with normal ankle brachial index or without a history of PAD. Family history of PAD was defined as having at least 1 first-degree relative who had undergone revascularization or stent placement for PAD before the age of 65 years. Logistic regression analyses were used to evaluate whether a family history of PAD was associated with the presence of PAD, independent of conventional risk factors. A family history of PAD was present more often in patients with PAD than in controls, with a resulting odds ratio (OR) of 2.20 (95% confidence interval [CI] 1.82 to 2.67). The association remained significant after adjustment for conventional risk factors (OR 1.97, 95% CI 1.60 to 2.42). The association was stronger in younger subjects (age <68 years; adjusted OR 2.46, 95% CI 1.79 to 3.38) than in older subjects (adjusted OR 1.61, 95% CI 1.22 to 2.12). A greater number of affected relatives with PAD was also associated with greater odds of presence of PAD (adjusted OR 1.86, 95% CI 1.48 to 2.33 and adjusted OR 2.56, 95% CI 1.60 to 4.11 for patients with 1 and ≥ 2 affected relatives with PAD, respectively). In conclusion, individuals with a family history of PAD have nearly double the odds of having PAD relative to those without such a history. | 25,107,577 | [
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Erythrocyte very long-chain saturated fatty acids associated with lower risk of incident sudden cardiac arrest. | Prior studies suggest that circulating n-3 and trans-fatty acids influence the risk of sudden cardiac arrest (SCA). Yet, while other fatty acids also differ in their membrane properties and biological activities which may influence SCA, little is known about the associations of other circulating fatty acids with SCA. The aim of this study was to investigate the associations of 17 erythrocyte membrane fatty acids with SCA risk. We used data from a population-based case-control study of SCA in the greater Seattle, Washington, area. Cases, aged 25-74 years, were out-of-hospital SCA patients, attended by paramedics (n=265). Controls, matched to cases by age, sex and calendar year, were randomly identified from the community (n=415). All participants were free of prior clinically-diagnosed heart disease. Blood was obtained at the time of cardiac arrest by attending paramedics (cases) or at the time of an interview (controls). Higher levels of erythrocyte very long-chain saturated fatty acids (VLSFA) were associated with lower risk of SCA. After adjustment for risk factors and levels of n-3 and trans-fatty acids, higher levels of 20:0 corresponding to 1 SD were associated with 30% lower SCA risk (13-43%, p=0.001). Higher levels of 22:0 and 24:0 were associated with similar lower SCA risk (ORs for 1 SD-difference: 0.71 [95% CI: 0.57-0.88, p=0.002] for 22:0; and 0.79 [95% CI: 0.63-0.98, p=0.04] for 24:0). These novel findings support the need for investigation of biologic effects of circulating VLSFA and their determinants. | 25,107,579 | [
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Leishmania molecules that mediate intracellular pathogenesis. | Parasites of the Leishmania genus are the causative agents of a complex disease called leishmaniasis. Many activities of infected cells including their responses to a range of stimuli are modulated by Leishmania parasites. This review will profile some of the parasite molecules that target host cell processes for which there has been recent progress. | 25,107,580 | [
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Vascular access in hemodialysis patients older than 80 years. | There is a worldwide surge in numbers of elderly people requiring hemodialysis accompanying the prevailing increase in longevity. There is a trend for central venous catheters to be preferentially placed in elderly patients, whereas others recommend routine use of grafts for surgical access. In our center, age has not been a consideration in deciding to construct arteriovenous access for hemodialysis. We reviewed our experience with arteriovenous access surgery in all hemodialysis patients aged 80 years and older to determine if this approach is justified in terms of patency and life expectancy. A retrospective study was made of all patients aged 80 years and older who had surgery from January 2005 to December 2009 at our national vascular access referral center. All patients had preoperative mapping and had fistula construction if the vein size was at least 3 mm. Otherwise they had brachiobasilic or brachioaxillary grafts. All patients had routine access surveillance by Doppler ultrasound (duplex) and physical examination at regular intervals, and interventions were carried out according to the findings. Type of access, success rate, maturation, primary and secondary patency, and patient survival in the age group older than 80 years were noted. During the study period, 134 patients had 146 new accesses. There were 128 autogenous accesses (30 forearm, 91 upper arm, and seven transposed basilic veins) and 18 prosthetic accesses. Overall primary patency was 39%, 33%, and 23% at 12, 24, and 36 months. Secondary patency was 92%, 83%, and 77% at 12, 24, and 36 months. There was no significant difference in patency between the different types of accesses and between diabetic and nondiabetic patients. Eleven upper arm and four forearm fistulas had delayed maturation or nonmaturation. The relative risk for delayed maturation or nonmaturation of forearm fistulas (13.3%) compared with brachial-cephalic fistula (12.1%) was 1.1030 (95% confidence interval, 0.3973-3.204; P = .8571). Median patient survival was 38 months, with 49 dying during follow-up. Contrary to recent recommendations favoring grafts for hemodialysis in patients older than 80 years, most elderly patients in this study were found to have vasculature that was suitable for autogenous access construction, with patency rates similar to those of their younger counterparts when adequate preoperative planning and postoperative maintenance were carried out. Age alone should not disqualify patients older than 80 years from access surgery for hemodialysis, nor should age disqualify these patients from the Fistula First Initiative. | 25,107,601 | [
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Clinical manifestations and prognostic factors of Morganella morganii bacteremia. | Although Morganella morganii causes a variety of clinical infections, there are limited studies on M. morganii bacteremia after the year 2000. A total of 109 patients with M. morganii bacteremia at a medical center in Taiwan from 2003 to 2012 were studied. Among them, 30.3 % had polymicrobial bacteremia and 75.2 % had community-acquired infection. The most common underlying diseases were hypertension (62.4 %) and diabetes mellitus (38.5 %). The urinary tract (41.3 %) was the major portal of entry, followed by the hepatobiliary tract (27.5 %), skin and soft tissue (21.1 %), and primary bacteremia (10.1 %). Susceptibility testing of M. morganii isolates showed ubiquitous resistance to first-generation cephalosporins and ampicillin-clavulanate; resistance rates to gentamicin, piperacillin-tazobactam, and ciprofloxacin were 30.3 %, 1.8 %, and 10.1 %, respectively. Overall, the 14-day mortality was 14.7 %. Univariate analysis revealed that elevated blood urea nitrogen (BUN) values [p = 0.0137, odds ratio (OR) 5.26], intensive care unit (ICU) admission (p = 0.011, OR 4.4), and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (p < 0.001, OR 1.62) were significantly associated with mortality. The APACHE II score remained the only significant risk factor for mortality in multivariate analysis (p = 0.0012, OR 1.55). In conclusion, M. morganii bacteremia patients were mostly elderly, with one or more comorbidities. Most of the patients had community-acquired infection via the urinary and hepatobiliary tracts. Furthermore, prognosis can be predicted according to disease severity measured by the APACHE II score. | 25,107,625 | [
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Photo-oxidation of tyrosine in a bio-engineered bacterioferritin 'reaction centre'-a protein model for artificial photosynthesis. | The photosynthetic reaction centre (RC) is central to the conversion of solar energy into chemical energy and is a model for bio-mimetic engineering approaches to this end. We describe bio-engineering of a Photosystem II (PSII) RC inspired peptide model, building on our earlier studies. A non-photosynthetic haem containing bacterioferritin (BFR) from Escherichia coli that expresses as a homodimer was used as a protein scaffold, incorporating redox-active cofactors mimicking those of PSII. Desirable properties include: a di-nuclear metal binding site which provides ligands for bivalent metals, a hydrophobic pocket at the dimer interface which can bind a photosensitive porphyrin and presence of tyrosine residues proximal to the bound cofactors, which can be utilised as efficient electron-tunnelling intermediates. Light-induced electron transfer from proximal tyrosine residues to the photo-oxidised ZnCe6(•+), in the modified BFR reconstituted with both ZnCe6 and Mn(II), is presented. Three site-specific tyrosine variants (Y25F, Y58F and Y45F) were made to localise the redox-active tyrosine in the engineered system. The results indicate that: presence of bound Mn(II) is necessary to observe tyrosine oxidation in all BFR variants; Y45 the most important tyrosine as an immediate electron donor to the oxidised ZnCe6(•+) and that Y25 and Y58 are both redox-active in this system, but appear to function interchangebaly. High-resolution (2.1Å) crystal structures of the tyrosine variants show that there are no mutation-induced effects on the overall 3-D structure of the protein. Small effects are observed in the Y45F variant. Here, the BFR-RC represents a protein model for artificial photosynthesis. | 25,107,631 | [
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Coverage of vitamin A supplementation and deworming during Malezi Bora in Kenya. | Twice-yearly child health weeks are an effective way of reaching children with essential child survival services in developing countries. In Kenya, child health weeks, or Malezi Bora, were restructured in 2007 from an outreach-based delivery structure to a health facility-based delivery structure to reduce delivery costs and increase sustainability of the events. Administrative data from 2007 to 2011 have demonstrated a decrease in coverage of Malezi Bora services to targeted children. A post-event coverage (PEC) survey was conducted after the May 2012 Malezi Bora to validate coverage of vitamin A supplementation (VAS) and deworming and to inform program strategy. Nine hundred caregivers with children aged 6-59months were interviewed using a randomized, 30×30 cluster design. For each cluster, one facility-based health worker and one community-based health worker were also interviewed. Coverage of VAS was 31.0% among children aged 6-59months and coverage of deworming was 19.6% among children aged 12-59months. Coverage of VAS was significantly higher for children aged 6-11months (45.7%, n=116) than for children aged 12-59months (28.8%, n=772) (p<0.01). Eighty-five percent (51/60) of health workers reported that Malezi Bora was implemented in their area while 23.6% of primary caregivers reported that Malezi Bora occurred in their area. The results of this PEC survey indicate that the existing Malezi Bora programmatic structure needs to be reviewed and reformed to meet WHO guidelines of 80% coverage with VAS. | 25,107,652 | [
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Low-contrast response deficits and increased neural noise in children with autism spectrum disorder. | A battery of short-duration neurophysiological tests were designed and implemented using visual evoked potentials (VEPs) to examine specific neural mechanisms in children with and without autism spectrum disorder (ASD). Contrast-sweep conditions (bright or dark isolated-checks) were used to elicit steady-state VEPs to examine the integrity of ON/OFF pathways. Children with ASD displayed deficits in low-contrast responses at the stimulus frequency of 12.5 Hz, notably under conditions that emphasized activity in the magnocellular pathway. Signal-to-noise ratios were weaker in the ASD group, particularly for the OFF pathway. There were no group differences in the amplitude of responses. In addition, the ASD group displayed significantly higher levels of neural noise than controls. For the response at the stimulus frequency, the ASD group produced a relatively constant level of noise across the contrast range tested, with higher levels than controls at low contrasts and approximately equal levels of noise at moderate to high contrasts. | 25,107,679 | [
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Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan: a national population-based study. | Children with epilepsy may have comorbidities that result in significant disability. Epidemiological information for pediatric patients with epilepsy in Taiwan is scant. This research estimates the prevalence and common neuro-psychiatric comorbidities of children with epilepsy in Taiwan. Patients aged less than 20 years old who had received a diagnosis of epilepsy and suffered from epileptic seizures in 2005 were identified in the NHIRD based on ICD-9-CM and prescription records for the use of at least one AED. We used cases of epileptic seizure to survey outpatient service data, and identify common neuro-psychiatric comorbidities. The crude prevalence rate and the age- and sex-specific prevalence were estimated. We also examined the effects of urbanization. The estimated prevalence of epilepsy was 0.33% in the pediatric population, with 0.29% for girls and 0.36% for boys. The most common neuropsychiatric comorbidities were learning disability and developmental delay, cerebral palsy, and mental retardation. Epilepsy was more prevalent in boys than in girls, especially among infants, preschool children, and those living in rural areas. In addition, boys with epilepsy had a higher rate of neurological comorbidities. The prevalence of psychiatric comorbidities was lower than that reported in previous studies performed in other countries, especially among children with epilepsy living in rural areas. This research provides the largest nationwide, population-based study of childhood epilepsy to estimate the prevalence and the associated neuropsychiatric comorbidities of pediatric epilepsy in Taiwan. Potential rural-urban disparity basing on prevalence and associated neuropsychiatric comorbidities cannot be ignored in Taiwan. | 25,107,685 | [
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MCL-1 dependency of cisplatin-resistant cancer cells. | The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings. | 25,107,702 | [
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The impact of intraoperative hypothermia on early postoperative adverse events after radical esophagectomy for cancer: a retrospective cohort study. | To investigate the correlation between intraoperative body temperature and postoperative adverse effects in patients who underwent esophagectomy procedures. Retrospective cohort study. University Hospital. One hundred twenty-one patients undergoing esophagectomy were enrolled. None. Various perioperative and intraoperative variables were recorded. Hypothermia was defined as a urinary bladder temperature<35°C. Multiple logistic regression analysis was conducted to identify independent significant predictors of postoperative complications. In addition, the authors also determined a cutoff point for intraoperative minimum urinary bladder temperature by analyzing receiver operating characteristic (ROC) curves for occurrence of adverse events at 1 month after surgery. No patients died within 1 month after the surgery. There were 53 patients with early postoperative complications, and 51 had experienced intraoperative hypothermia. Factors that were correlated significantly with complications included age (p=0.02); hypothermia (p<0.01); and doses of ephedrine (p<0.01), phenylephrine (p<0.01), and fentanyl (p<0.01). Multiple logistic regression analysis identified intraoperative hypothermia as a significant independent predictor for the development of early perioperative complications (odds ratio 2.57; 95% confidence interval 1.09-6.08). The area under the ROC curve for body temperature was 0.71, and the cutoff point was 35°C (sensitivity=0.65, specificity=0.72). Intraoperative hypothermia was identified as an independent risk factor for early postoperative adverse events following esophagectomy. | 25,107,714 | [
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Time up and go task performance improves after transcranial direct current stimulation in patient affected by Parkinson's disease. | Locomotor disturbances represent one of the major distress in everyday life in people with Parkinson's disease (PD). Timed up and go test (TUG) has been advocated a useful and reliable tool for quantifying locomotor performance. The aim of this study was to assess the effect of anodal transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) during timed up and go test (TUG) in a group of patients with PD. Ten participants underwent two sessions of anodal tDCS (left and right) and one session of placebo tDCS. TUG was performed before and after each tDCS session (anodal or placebo). A significant motor improvement after right DLPFC stimulation vs. placebo stimulation was observed. These results suggest that anodal tDCS can be a relevant tool to modulate walking abilities in PD. | 25,107,738 | [
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Prognostic factors and course for successful clinical outcome quality of life and patients' perceived effect after a cognitive behavior therapy for chronic non-specific low back pain: A 12-months prospective study. | This study investigates the clinical course of and prognostic factors for quality of life (Short Form 36 items Health survey (SF-36)) and global perceived effect (GPE) in patients treated for chronic non-specific low back pain at 5 and 12-months follow-up. Data from a prospective cohort (n = 1760) of a rehabilitation center were used, where patients followed a 2-months cognitive behavior treatment. The outcome 'improvement in quality of life (SF-36)' was defined as a 10% increase in score on the SF-36 at follow-up compared with baseline. On the GPE scale, patients who indicated to be 'much improved' were coded as 'clinically improved'. Multivariable logistic regression analysis included 23 baseline characteristics. At 5-months follow-up, scores on the SF-36 Mental Component Scale (SF-36; MCS) and the Physical Component Scale (SF-36; PCS) had increased from 46.6 (SD 10.3) to 50.4 (SD 9.8) and from 31.9 (SD 7.1) to 46.6 (SD 10.3), respectively. At 5-months follow-up, 53.0% of the patients reported clinical improvement (GPE) which increased to 60.3% at 12-months follow-up. The 10% improvement in quality of life (SF-36 MCS) at 5-months follow-up was associated with patient characteristics and psychological factors. At 5-months follow-up, the 10% improvement in quality of life (SF-36 PCS) and GPE was associated with patient characteristics, physical examination, work-related factors and psychological factors; for GPE, an association was also found with clinical status. At 12-months follow-up GPE was associated with patient characteristics, clinical status, physical examination and work-related factors. The next phase in this prognostic research is external validation of these results. | 25,107,827 | [
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Delivery of lipophilic porphyrin by liposome vehicles: preparation and photodynamic therapy activity against cancer cell lines. | Porphyrin photosensitizers are mostly used components in photodynamic therapy (PDT). The poor solubility of porphyrins in aqueous medium is the problem to be solved for the in vivo applications. The delivery of photosensitizers to the tumor cells using liposome vehicles can help to overcome this problem. In this work, we have first functionalized the protoporphyrin IX with lipophilic oleylamine arms and encapsulated it into 1,2 dioleyl-sn-glycero-phosphatidylcholine (DOPC) liposomes. The appropriate sizes of liposomes are about 140 nm and have the characteristic Soret and Q band absorptions at 405 nm (Soret), 507 nm, 541 nm, 577 nm and 631 nm (Q bands), respectively. In the photodynamic activity studies, the liposomal porphyrins were irradiated with light (375 nm, 10 mW) in the presence of cancer cell lines, HeLa and AGS. We have found that both liposomal porphyrins and oleylamine conjugated porphyrins are much more effective than PpIX. This result can be attributed to the drug delivery characteristic of the liposomes which plays effective role in endocytosis. We also found that, in AGS cells, liposomal PpIX-Ole induced apoptosis more than HeLa cells under light conditions. | 25,107,838 | [
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(19)F applications in drug development and imaging - a review. | To control drugs in vivo, new approaches are needed. Considerable progress has been made towards the applications of fluorine ((19)F) in pharmacotherapy in this regard. To date, many authors have showed that by using (19)F labelled drugs and non-invasive magnetic resonance imaging (MRI) techniques together, drug biodistribution can be tracked. This review presents methods for (19)F incorporation into pharmaceuticals by forming C-F bonds and drug fluorine oil-water emulsions. Inadequate drug delivery is a major cause of drug resistance, which can be improved using approaches discussed herein aided by (19)F MRI. | 25,107,839 | [
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IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling. | Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKKβ), the critical activating kinase in canonical (NFκB) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKβ and K171T IKKβ represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKβ contributes to lymphomagenesis. | 25,107,905 | [
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A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology. | Mucolipidosis II (MLII) is a lysosomal storage disorder caused by loss of N-acetylglucosamine-1-phosphotransferase, which tags lysosomal enzymes with a mannose 6-phosphate marker for transport to the lysosome. In MLII, the loss of this marker leads to deficiency of multiple enzymes and non-enzymatic proteins in the lysosome, leading to the storage of multiple substrates. Here we present a novel mouse model of MLII homozygous for a patient mutation in the GNPTAB gene. Whereas the current gene knock-out mouse model of MLII lacks some of the characteristic features of the human disease, our novel mouse model more fully recapitulates the human pathology, showing growth retardation, skeletal and facial abnormalities, increased circulating lysosomal enzymatic activities, intracellular lysosomal storage, and reduced life span. Importantly, MLII behavioral deficits are characterized for the first time, including impaired motor function and psychomotor retardation. Histological analysis of the brain revealed progressive neurodegeneration in the cerebellum with severe Purkinje cell loss as the underlying cause of the ataxic gait. In addition, based on the loss of Npc2 (Niemann-Pick type C 2) protein expression in the brain, the mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of Niemann-Pick type C disease. No improvement in brain pathology was observed. This indicates that cerebellar degeneration is not primarily triggered by loss of Npc2 function. This study emphasizes the value of modeling MLII patient mutations to generate clinically relevant mouse mutants to elucidate the pathogenic molecular pathways of MLII and address their amenability to therapy. | 25,107,912 | [
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Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. | During tumor development, tumor cells constantly communicate with the surrounding microenvironment through both biochemical and biophysical cues. In particular, the tumor microenvironment can instruct carcinoma cells to undergo a morphogenesis program termed epithelial-to-mesenchymal transition (EMT) to facilitate local invasion and metastatic dissemination. Growing evidence uncovered a plethora of microenvironmental factors in promoting EMT, including proinflammatory cytokines secreted by locally activated stromal cells, hypoxia conditions, extracellular matrix components, and mechanical properties. Here, we review various biochemical and biophysical factors in the tumor microenvironment that directly impinge upon the EMT program. Specifically, cytokines such as TGFβ, TNFα, and IL6 and hypoxia are capable of inducing EMT in various tumors. Several extracellular matrix (ECM) proteins, including collagen-I, fibronectin, and hyaluronan, and ECM remodeling via extracellular lysyl oxidase are also implicated in regulating EMT. In preclinical studies and ongoing clinical trials, targeting these tumor microenvironmental signals has shown promises in halting tumor progression in various human cancers. | 25,107,915 | [
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Membrane dynamics at the nuclear exchange junction during early mating (one to four hours) in the ciliate Tetrahymena thermophila. | Using serial-section transmission electron microscopy and three-dimensional (3D) electron tomography, we characterized membrane dynamics that accompany the construction of a nuclear exchange junction between mating cells in the ciliate Tetrahymena thermophila. Our methods revealed a number of previously unknown features. (i) Membrane fusion is initiated by the extension of hundreds of 50-nm-diameter protrusions from the plasma membrane. These protrusions extend from both mating cells across the intercellular space to fuse with membrane of the mating partner. (ii) During this process, small membrane-bound vesicles or tubules are shed from the plasma membrane and into the extracellular space within the junction. The resultant vesicle-filled pockets within the extracellular space are referred to as junction lumens. (iii) As junction lumens fill with extracellular microvesicles and swell, the plasma membrane limiting these swellings undergoes another deformation, pinching off vesicle-filled vacuoles into the cytoplasm (reclamation). (iv) These structures (resembling multivesicular bodies) seem to associate with autophagosomes abundant near the exchange junction. We propose a model characterizing the membrane-remodeling events that establish cytoplasmic continuity between mating Tetrahymena cells. We also discuss the possible role of nonvesicular lipid transport in conditioning the exchange junction lipid environment. Finally, we raise the possibility of an intercellular signaling mechanism involving microvesicle shedding and uptake. | 25,107,923 | [
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Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. | The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have come to realise that permselectivity depends on size and not necessarily charge, that the molecular sieve depends on the podocyte contractile apparatus and is highly dynamic, and that protein uptake by proximal tubular epithelial cells stimulates signalling and the production of transcription factors and inflammatory mediators. Alport syndrome is the second commonest monogenic cause of renal failure after autosomal dominant polycystic kidney disease. Eighty per cent of patients have X-linked disease caused by mutations in the COL4A5 gene. Most of these result in the replacement of the collagen IV α3α4α5 network with the α1α1α2 heterotrimer. Affected membranes also have ectopic laminin and increased matrix metalloproteinase levels, which makes them more susceptible to proteolysis. Mechanical stress, due to the less elastic membrane and hypertension, interferes with integrin-mediated podocyte-GBM adhesion. Proteinuria occurs when urinary levels exceed tubular reabsorption rates, and initiates tubulointerstitial fibrosis. The glomerular mesangial cells produce increased TGFβ and CTGF which also contribute to glomerulosclerosis. Currently there is no specific therapy for Alport syndrome. However treatment with angiotensin converting enzyme (ACE) inhibitors delays renal failure progression by reducing intraglomerular hypertension, proteinuria, and fibrosis. Our greater understanding of the mechanisms underlying the GBM changes and their consequences in Alport syndrome have provided us with further novel therapeutic targets. | 25,107,927 | [
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Different effects of transgenic maize and nontransgenic maize on nitrogen-transforming archaea and bacteria in tropical soils. | The composition of the rhizosphere microbiome is a result of interactions between plant roots, soil, and environmental conditions. The impact of genetic variation in plant species on the composition of the root-associated microbiota remains poorly understood. This study assessed the abundances and structures of nitrogen-transforming (ammonia-oxidizing) archaea and bacteria as well as nitrogen-fixing bacteria driven by genetic modification of their maize host plants. The data show that significant changes in the abundances (revealed by quantitative PCR) of ammonia-oxidizing bacterial and archaeal communities occurred as a result of the maize host being genetically modified. In contrast, the structures of the total communities (determined by PCR-denaturing gradient gel electrophoresis) were mainly driven by factors such as soil type and season and not by plant genotype. Thus, the abundances of ammonia-oxidizing bacterial and archaeal communities but not structures of those communities were revealed to be responsive to changes in maize genotype, allowing the suggestion that community abundances should be explored as candidate bioindicators for monitoring the possible impacts of cultivation of genetically modified plants. | 25,107,970 | [
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Vibrio harveyi adheres to and penetrates tissues of the European abalone Haliotis tuberculata within the first hours of contact. | Vibrio harveyi is a marine bacterial pathogen responsible for episodic epidemics generally associated with massive mortalities in many marine organisms, including the European abalone Haliotis tuberculata. The aim of this study was to identify the portal of entry and the dynamics of infection of V. harveyi in the European abalone. The results indicate that the duration of contact between V. harveyi and the European abalone influences the mortality rate and precocity. Immediately after contact, the epithelial and mucosal area situated between the gills and the hypobranchial gland was colonized by V. harveyi. Real-time PCR analyses and culture quantification of a green fluorescent protein-tagged strain of V. harveyi in abalone tissues revealed a high density of bacteria adhering to and then penetrating the whole gill-hypobranchial gland tissue after 1 h of contact. V. harveyi was also detected in the hemolymph of a significant number of European abalones after 3 h of contact. In conclusion, this article shows that a TaqMan real-time PCR assay is a powerful and useful technique for the detection of a marine pathogen such as V. harveyi in mollusk tissue and for the study of its infection dynamics. Thus, we have revealed that the adhesion and then the penetration of V. harveyi in European abalone organs begin in the first hours of contact. We also hypothesize that the portal of entry of V. harveyi in the European abalone is the area situated between the gills and the hypobranchial gland. | 25,107,972 | [
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Obesity and physical activity in children of immigrants. | Childhood overweight and obesity have increased in recent decades, reaching alarming proportions. Children with a migrant background seem to be particularly at risk of developing overweight and obesity. This article provides an overview of the prevalence of overweight or obesity among North African (NA) children living in their own countries or as immigrants in Europe. The aim is to show the effect of the migration process on this trend and to discuss its possible contributing factors. Publications were identified by a systematic search of PubMed and the existing literature. Original longitudinal or cross-sectional studies on the prevalence of childhood and adolescent overweight and obesity and of physical activity among ethnic groups from North Africa compared with the native population were reviewed. The results confirmed that children of NA origin in Europe have higher levels of overweight and obesity than the native ones, especially girls. However, this trend can also be detected in urban areas of NA countries. Important factors contributing to the increase of overweight and obesity among children and adolescents are discussed, in particular the westernization of eating habits, the level of physical activity and body image perception. The review shows that factors linked to acculturation in the host society and others maintained from the country of origin come into play in determining childhood overweight and obesity among NA immigrants in Europe. The importance of health promotion targeting the groups most at risk of childhood overweight and obesity, i.e. aspects of a healthy diet and the benefits of physical activity, is underlined. | 25,107,997 | [
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Consanguinity and genetic diseases in North Africa and immigrants to Europe. | Endemic diseases are caused by environmental and genetic factors. While in this special issue several chapters deal with environmental factors, including infections, the present focus is on genetic causes of disease clustering due to inbreeding and recessive disease mechanisms. Consanguinity is implying sharing of genetic heritage because of marriage between close relatives originating from a common ancestor. With limited natural selection, recessive genes may become more frequent in an inbred compared with an outbred population. Consanguinity is common in North Africa (NA), and the estimates range from 40 to 49% of all marriages in Tunisia and 29-33% in Morocco. As a consequence, recessive disorders are common in the NA region, and we give some examples. Thalassaemia and sickle cell disease/anaemia constitute the most common inherited recessive disorders globally and they are common in NA, but with immigration they have spread to Europe and to other parts of the world. Another example is familial Mediterranean fever, which is common in the Eastern Mediterranean area. With immigrantion from that area to Sweden, it has become the most common hereditary autoinflammatory disease in that country, and there is no evidence that any native Swede would have been diagnosed with this disease. The examples discussed in this chapter show that the historic movement of populations and current immigration are influencing the concept of 'endemic' disease. | 25,107,999 | [
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Metabolic hyperemia requires ATP-sensitive K+ channels and H2O2 but not adenosine in isolated mouse hearts. | We have previously demonstrated that adenosine-mediated H2O2 production and opening of ATP-sensitive K(+) (KATP) channels contributes to coronary reactive hyperemia. The present study aimed to investigate the roles of adenosine, H2O2, and KATP channels in coronary metabolic hyperemia (MH). Experiments were conducted on isolated Langendorff-perfused mouse hearts using combined pharmacological approaches with adenosine receptor (AR) knockout mice. MH was induced by electrical pacing at graded frequencies. Coronary flow increased linearly from 14.4 ± 1.2 to 20.6 ± 1.2 ml·min(-1)·g(-1) with an increase in heart rate from 400 to 650 beats/min in wild-type mice. Neither non-selective blockade of ARs by 8-(p-sulfophenyl)theophylline (8-SPT; 50 μM) nor selective A2AAR blockade by SCH-58261 (1 μM) or deletion affected MH, although resting flow and left ventricular developed pressure were reduced. Combined A2AAR and A2BAR blockade or deletion showed similar effects as 8-SPT. Inhibition of nitric oxide synthesis by N-nitro-l-arginine methyl ester (100 μM) or combined 8-SPT administration failed to reduce MH, although resting flows were reduced (by ∼20%). However, glibenclamide (KATP channel blocker, 5 μM) decreased not only resting flow (by ∼45%) and left ventricular developed pressure (by ∼36%) but also markedly reduced MH by ∼94%, resulting in cardiac contractile dysfunction. Scavenging of H2O2 by catalase (2,500 U/min) also decreased resting flow (by ∼16%) and MH (by ∼24%) but to a lesser extent than glibenclamide. Our results suggest that while adenosine modulates coronary flow under both resting and ischemic conditions, it is not required for MH. However, H2O2 and KATP channels are important local control mechanisms responsible for both coronary ischemic and metabolic vasodilation. | 25,108,010 | [
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Role of blood and vascular smooth muscle in the vasoactivity of nitrite. | Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin. | 25,108,012 | [
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Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice. | The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases. | 25,108,020 | [
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In vitro PAMAM, phosphorus and viologen-phosphorus dendrimers prevent rotenone-induced cell damage. | We have investigated whether polyamidoamine (PAMAM), phosphorus (pd) and viologen-phosphorus (vpd) dendrimers can prevent damage to embryonic mouse hippocampal cells (mHippoE-18) caused by rotenone, which is used as a pesticide, insecticide, and as a nonselective piscicide, that works by interfering with the electron transport chain in mitochondria. Several basic aspects, such as cell viability, production of reactive oxygen species and changes in mitochondrial transmembrane potential, were analyzed. mHippoE-18 cells were treated with these structurally different dendrimers at 0.1μM. A 1h incubation with dendrimers was followed by the addition of rotenone at 1μM, and a further 24h incubation. PAMAM, phosphorus and viologen-phosphorus dendrimers all increased cell viability (reduced cell death-data need to be compared with untreated controls). A lower level of reactive oxygen species and a favorable effect on mitochondrial system were found with PAMAM and viologen-phosphorus dendrimers. These results indicate reduced toxicity in the presence of dendrimers. | 25,108,046 | [
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Cardiovascular and autonomic responses to whole-body cryostimulation in essential hypertension. | Over recent years, a considerable increase in the popularity of cryostimulation and whole body cryotherapy (WBC) procedures has occurred both among healthy individuals and in various groups of patients, including those with primary untreated hypertension. The aim of this study was to compare the effects of WBC on the functional parameters of cardiovascular system in normotensive and primarily hypertensive individuals. The study included 26 young male volunteers with normal blood pressure range (NormoBP) and 13 with essential arterial hypertension (HyperBP). Each subject was exposed to cryotherapeutic factor (whole-body cryotherapy/cryostimulation, WBC) at a temperature of approximately -115°C to -125°C for a period of 3 min. The cardiovascular and autonomic parameters were measured noninvasively with Task Force® Monitor. Measurements in a supine position and tilt test were performed "before WBC" and "after WBC". Our study revealed that cryogenic temperatures exert strong modulatory effect on the cardiovascular system. Both groups showed adaptive changes of myocardial and vascular parameters in response to rapid cooling of virtually the whole body surface. While the profiles of some of these changes were similar in both the groups, also several considerable intergroup differences were documented. Consequently, the cryostimulation and cryotherapy treatment should be prescribed carefully to individuals who present with cardiovascular failure of any degree. | 25,108,050 | [
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A critical appraisal of existing concepts for the grouping of nanomaterials. | The grouping of substances serves to streamline testing for regulatory purposes. General grouping approaches for chemicals have been implemented in, e.g., the EU chemicals regulation. While specific regulatory frameworks for the grouping of nanomaterials are unavailable, this topic is addressed in different publications, and preliminary guidance is provided in the context of substance-related legislation or the occupational setting. The European Centre for Ecotoxicology and Toxicology of Chemicals Task Force on the Grouping of Nanomaterials reviewed available concepts for the grouping of nanomaterials for human health risk assessment. In their broad conceptual design, the evaluated approaches are consistent or complement each other. All go beyond the determination of mere structure-activity relationships and are founded on different aspects of the nanomaterial life cycle. These include the NM's material properties and biophysical interactions, specific types of use and exposure, uptake and kinetics, and possible early and apical biological effects. None of the evaluated grouping concepts fully take into account all of these aspects. Subsequent work of the Task Force will aim at combining the available concepts into a comprehensive 'multiple perspective' framework for the grouping of nanomaterials that will address all of the mentioned aspects of their life cycles. | 25,108,058 | [
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Localization of ocular albinism-1 gene product GPR143 in the rat central nervous system. | L-3,4-Dihydroxyphenylalanine (DOPA) has been believed to be a precursor of dopamine, and itself being an inert amino acid. Previously, we have proposed DOPA as a neurotransmitter candidate in the central nervous system (CNS). Recent findings have suggested DOPA as an endogenous agonist of a G-protein coupled receptor, ocular albinism 1 gene product (OA1), which is highly expressed in the retinal pigmental epithelium. However, whether OA1 functions as a receptor for DOPA in vivo, and whether this receptor-ligand interaction is responsible for a wide variety of DOPA actions have not been determined yet. To gain insight into the functional implication of OA1, we perform immunohistochemical examination with anti-OA1 antibody to localize OA1 in the adult rat brain. We observed OA1 immunoreactive cells in the hippocampus, cerebral cortex, cerebellum cortex, striatum, substantia nigra, hypothalamic median eminence and supraoptic nucleus, nucleus tractus solitarii and caudal ventrolateral medulla and rostral ventrolateral medulla, medial habenular nucleus and olfactory bulb. This study reveals, for the first time, the unique distribution pattern of OA1-immunoreactive neurons and/or cells in the rat CNS. | 25,108,060 | [
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Progesterone production is affected by unfolded protein response (UPR) signaling during the luteal phase in mice. | We examined whether the three unfolded protein response (UPR) signaling pathways, which are activated in response to endoplasmic reticulum (ER)-stress, are involved in progesterone production in the luteal cells of the corpus luteum (CL) during the mouse estrous cycle. The luteal phase of C57BL/6 female mice (8 weeks old) was divided into two stages: the functional stage (16, 24, and 48 h) and the regression stage (72 and 96 h). Western blotting and reverse transcription (RT)-PCR were performed to analyze UPR protein/gene expression levels in each stage. We investigated whether ER stress affects the progesterone production by using Tm (0.5 μg/g BW) or TUDCA (0.5 μg/g BW) through intra-peritoneal injection. Our results indicate that expressions of Grp78/Bip, p-eIF2α/ATF4, p50ATF6, and p-IRE1/sXBP1 induced by UPR activation were predominantly maintained in functional and early regression stages of the CL. Furthermore, the expression of p-JNK, CHOP, and cleaved caspase3 as ER-stress mediated apoptotic factors increased during the regression stage. Cleaved caspase3 levels increased in the late-regression stage after p-JNK and CHOP expression in the early-regression stage. Additionally, although progesterone secretion and levels of steroidogenic enzymes decreased following intra-peritoneal injection of Tunicamycin, an ER stress inducer, the expression of Grp78/Bip, p50ATF6, and CHOP dramatically increased. These results suggest that the UPR signaling pathways activated in response to ER stress may play important roles in the regulation of the CL function. Furthermore, our findings enhance the understanding of the basic mechanisms affecting the CL life span. | 25,108,065 | [
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Synthesis and biological evaluations of new analogs of 2-methoxyestradiol: inhibitors of tubulin and angiogenesis. | The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 15 analogs of 2-methoxyestradiol (1) are reported. The biological studies revealed that the position of nitrogen atom in the heterocyclic ring is important for inhibition of both tubulin polymerization and angiogenesis. The most potent inhibitors were compounds 11f and 13e, with a 6-substituted isoquinoline ring in the 17-position of the steroid skeleton. Moreover, low estrogen activity was observed for the analogs tested at 10 μM concentrations. | 25,108,078 | [
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Synthesis and biological evaluation of novel thieno[2,3-d]pyrimidine-based FLT3 inhibitors as anti-leukemic agents. | The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents. | 25,108,079 | [
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