title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Refractory benign esophageal strictures: extending the role of expandable stents. | It is challenging to manage benign refractory esophageal strictures. We have now moved on from instant dilators to prolonged gradual dilatations using expandable stents that can be removed or biodegradable after a period of time left in situ. Recent published experience and the present study by Dua et al. have demonstrated the feasibility of this technique. However, not all strictures are the same and several issues need to be addressed including stent migration, stent duration, and the sub-group of patients who will benefit most. | 18,786,109 |
Wireless pH recording immediately above the squamocolumnar junction improves the diagnostic performance of esophageal pH studies. | The optimal position for pH electrode placement in the diagnosis of gastroesophageal reflux disease (GERD) is unknown. The aim of this study was to evaluate the discriminatory power of targeted pH recording immediately above the squamocolumnar junction (SCJ) and to compare the results with those obtained by simultaneous recording at the conventional level for pH monitoring. Sixty-two patients with typical reflux symptoms and 49 asymptomatic volunteers underwent 48-h simultaneous wireless pH monitoring with two endoscopically placed pH recording capsules, one immediately above the SCJ and one at the traditional position, 6 cm above the SCJ. The diagnostic accuracy, sensitivity, and specificity of pH monitoring at the two levels were analyzed using receiver operating characteristics (ROC) curves. Of the 62 patients (39 men and 23 women, median age 48 yrs), 32 patients had erosive esophagitis and 30 had no endoscopic evidence of mucosal injury. Analysis of the area under the ROC curve (AUC) indicated that the total percent time with pH<4 for the entire 48-h period was the parameter that best distinguished GERD patients from controls. pH monitoring performed directly above the SCJ significantly increased the number of patients correctly classified with GERD compared to standard electrode placement. With a predefined test specificity of 90%, pH monitoring immediately above the SCJ increased the sensitivity of the test from 63% to 86% in all patients, from 78% to 97% in patients with esophagitis and from 47% to 73% in patients with no esophagitis. Compared to standard electrode placement, wireless pH recording immediately above the SCJ improved the diagnostic performance of esophageal pH monitoring in patients with GERD. | 18,786,112 |
Transcription factors Sp1 and C/EBP regulate NRAMP1 gene expression. | The natural resistance-associated macrophage protein 1 (Nramp1), which belongs to a conserved family of membrane metal transporters, contributes to phagocyte-autonomous antimicrobial defense mechanisms. Genetic polymorphisms in the human NRAMP1 gene predispose to susceptibility to infectious or inflammatory diseases. To characterize the transcriptional mechanisms controlling NRAMP1 expression, we previously showed that a 263 bp region upstream of the ATG drives basal promoter activity, and that a 325 bp region further upstream confers myeloid specificity and activation during differentiation of HL-60 cells induced by vitamin D. Herein, the major transcription start site was mapped in the basal region by S1 protection assay, and two cis-acting elements essential for myeloid transactivation were characterized by in vitro DNase footprinting, electrophoretic mobility shift experiments, in vivo transfection assays using linker-mutated constructs, and chromatin immunoprecipitation assays in differentiated monocytic cells. One distal cis element binds Sp1 and is required for NRAMP1 myeloid regulation. Another site in the proximal region binds CCAAT enhancer binding proteins alpha or beta and is crucial for transcription. This study implicates Sp1 and C/EBP factors in regulating the expression of the NRAMP1 gene in myeloid cells. | 18,786,141 |
Localization of general and regulatory proteolysis in Bacillus subtilis cells. | Protein degradation mediated by ATP-dependent proteases, such as Hsp100/Clp and related AAA+ proteins, plays an important role in cellular protein homeostasis, protein quality control and the regulation of, e.g. heat shock adaptation and other cellular differentiation processes. ClpCP with its adaptor proteins and other related proteases, such as ClpXP or ClpEP of Bacillus subtilis, are involved in general and regulatory proteolysis. To determine if proteolysis occurs at specific locations in B. subtilis cells, we analysed the subcellular distribution of the Clp system together with adaptor and general and regulatory substrate proteins, under different environmental conditions. We can demonstrate that the ATPase and the proteolytic subunit of the Clp proteases, as well as the adaptor or substrate proteins, form visible foci, representing active protease clusters localized to the polar and to the mid-cell region. These clusters could represent a compartmentalized place for protein degradation positioned at the pole close to where most of the cellular protein biosynthesis and also protein quality control are taking place, thereby spatially separating protein synthesis and degradation. | 18,786,145 |
The porcine fat mass and obesity associated (FTO) gene is associated with fat deposition in Italian Duroc pigs. | In humans, common variants in the fat mass and obesity associated (FTO) gene are associated with body mass index and obesity. Here we sequenced exon 4, parts of introns 3 and 4 and two portions of the 3'-untranslated region of the porcine FTO gene in a panel of nine pigs of different breeds and identified three SNPs. Allele frequencies of the g.276T>G (AM931150) mutation were studied in seven pig breeds. This mutation was used to linkage-map FTO to SSC6. Association analyses between the g.276T>G polymorphism and several traits [pH of semimembranosus muscle and estimated breeding values (EBV) for average daily gain, back fat thickness, lean cuts, ham weight and feed:gain ratio] were carried out in 257 sib-tested Italian Large White pigs. Only feed:gain ratio showed P<0.05. A selective genotyping approach was applied, analysing two extreme and divergent groups of Italian Large White pigs selected on the basis of back fat thickness EBV (50 with most positive and 50 with most negative values). Fisher's exact test (two-tailed) was not significant when comparing the allele frequencies of these two groups. The same approach was used in the Italian Duroc breed for which two extreme and divergent groups of animals were selected according to visible intermuscular fat EBV. Differences of allele frequencies between these two groups were highly significant (P<0.00001, P<0.001 and P<0.0001, considering all animals or only two- or three-generation unrelated animals respectively), indicating association between the analysed FTO marker and intermuscular fat deposition. | 18,786,155 |
Opioidergic regulation of astroglial/neuronal proliferation: where are we now? | Opiate drugs, such as codeine, morphine, and heroin, are powerful analgesics, but also are used as drugs of abuse because of their psychogenic properties. Many studies have shown that opiates impact on cellular proliferation in the adult and developing brain, although anatomical pathologies are lacking in in utero exposed infants and opioid knockout mice. Recent research has defined a context-dependent role for the opioid system in neurogenesis in the adult hippocampus with exercise. Opioids have been shown to interact with proliferating cells of the postnatal subventricular zone of the lateral ventricles. The subventricular zone is also a region of adult neurogenesis, a fact that was not well established at the time this earlier research was conducted. Although a relationship between opioids and fetal neurogenesis has yet to be firmly established, many studies have implicated the opioid system in this process. One common factor that links neurogenesis in adult, postnatal, and fetal structures is the involvement of neuronal progenitor cells of the astrocytic lineage. It is therefore of interest that opioids have been consistently shown to impact upon astrocytic proliferation. It is the intention of this paper to review the literature that has established a role for the opioid system in neurogenesis in vivo in fetal, postnatal, and adult animals and to examine the links of opioids to modulation of astrocytic proliferation. | 18,786,168 |
Neuroprotective effect of sonic hedgehog up-regulated in Schwann cells following sciatic nerve injury. | The physiological roles of sonic hedgehog (Shh) have been intensively characterized in development of various organs. However, their functions in adult tissues have not been fully elucidated. We investigated the expression and the potential function of Shh in crush-injured adult rat sciatic nerves. The Shh expression was up-regulated in Schwann cells adjacent to the injured site. The time-course analyses of various neurotrophic factors revealed the up-regulation of Shh mRNA followed by that of brain-derived neurotrophic factor (BDNF) mRNA. The continuous administration of cyclopamine, a hedgehog signal inhibitor, to the injured site suppressed the increase of BDNF expression and deteriorated the survival of motor neurons in lumbar spinal cord. Treatment of exogenous Shh in cultured Schwann cells enhanced the BDNF expression. The BDNF promoter activity (exon I and II) was increased in IMS32 cells co-transfected with Shh and its receptor Smoothened. These findings imply that the up-regulated expression of Shh in Schwann cells may play an important role in injured motor neurons through the induction of BDNF. | 18,786,173 |
VEGFR-2-mediated increased proliferation and survival in response to oxygen and glucose deprivation in PlGF knockout astrocytes. | In hypoxic/ischemic conditions, astrocytes are involved in neuroprotection and angiogenesis. Vascular endothelial growth factor (VEGF) induces angiogenesis and exhibits neuroprotective and neurotrophic properties. However, the role of placental growth factor (PlGF), a VEGF homolog, in these processes is unclear. Therefore, proliferation and survival studies were performed on PlGF knockout (PlGF-/-) and wild-type (PlGF+/+) mouse astrocytes. A significant increase in cell proliferation and survival to oxygen and glucose deprivation (OGD) was observed in PlGF-/- compared to PlGF+/+ astrocytes. Interestingly, no PlGF protein expression was detected in PlGF+/+ astrocytes and no changes in VEGF protein levels were observed between the two genotypes. Real-time PCR and immunocytochemistry showed over-expression of VEGF receptor-2 (VEGFR-2) in PlGF-/- compared with PlGF+/+ astrocytes. Confocal microscopy revealed nuclear, membrane, and cytoplasmic localization of VEGFR-2. In vivo over-expression of VEGFR-2 mRNA was also detected in PlGF-/- compared with PlGF+/+ astrocytes. Stimulation with VEGF165 resulted in increased proliferation in PlGF-/- compared with PlGF+/+ astrocytes. This effect was blocked by the VEGFR-2 antagonist, VEGF165b. The enhanced proliferation of PlGF-/- astrocytes correlated with increased phospho-extracellular-signal-regulated kinase-1/2 levels, while the resistance to OGD was independent of the phosphatidylinositol 3'-kinase/Akt pathway. These results suggest that VEGFR-2 mediates the enhanced proliferative/OGD resistant phenotype observed in PlGF-/- astrocytes. | 18,786,179 |
Penile malignant melanoma in a hemodialysis patient. | A patient who was receiving hemodialysis treatment developed melanotic macules on the surface of the penis in 2002 and showed a tumor-like mass in the same region in July 2006. The patient presented with a pedunculated tumor of 3 cm in diameter on the right side of his penis. The tumor was resected for biopsy and was diagnosed as malignant melanoma. The melanoma was in stage IIIB with pT4 N1 M0. The patient received interferon-beta for a total of three courses. A computed tomography scan in the 10th postoperative month did not find any additional metastatic foci or recurrence of the tumor. In the present case, side effects caused by interferon were not observed. Therefore, particularly in dialysis patients, immune therapy might be favored over anticancer drug treatment. | 18,786,196 |
Personality disorders: illegitimate subject positions. | The diagnosis of personality disorder is common in mental health nurse settings and is a term often used without critical consideration. In clinical practice, the term personality disorder has pejorative connotations, which arise out of the way in which these behaviours are constructed as behavioural rather than psychiatric. The discursive construction of categories of personality disorder are inculcated into clinical practice and become taken-for-granted by those in practice culture. The construction of some personalities as disordered and, therefore, illegitimate becomes natural. This paper provides a critical analysis of the diagnosis and suggests an approach to mental health nursing care that is more legitimizing for those people who receive psychiatric diagnoses. | 18,786,214 |
Humanism in forensic psychiatry: the use of the tidal nursing model. | The humanist school of thought, which finds resonance in many conceptual models and theories designed to guide nursing practice, needs to be understood in the context of the total institution, where the individual is subjected to a mortification of the self, and denied autonomy. This article will engage in a critical reflection on how humanism has influenced nursing theorists and the subsequent production of conceptual models and theories, especially as they relate to the field of forensic psychiatric nursing. Although humanism provides optimism for nurse-patient relations, this article explores the incapability of such a philosophy to acknowledge the power relationships between individuals and its inability to explain the day-to-day realities experienced in forensic nursing, where the possibility of interpersonal violence reshapes nursing care. The tidal model will be discussed in detail as an example of a recently developed humanistic nursing model. Viewed from this perspective, it is clear that humanistic philosophy and its subsequent models of care are in discordance with the highly specialized field of forensic nursing. | 18,786,215 |
Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. | New onset diabetes after transplantation (NODAT) and impaired fasting glucose (IFG) are common in kidney transplant recipients (KTRs). Calcinuerin inhibitor (CNI) therapy is a causal risk factor. NODAT is associated with increased mortality and diminished graft survival. We studied the incidence of NODAT and IFG in KTRs before and after a medically indicated switch of CNI therapy from cyclosporine (CsA) to tacrolimus (Tac). The study population consisted of 704 nondiabetic KTRs. Of them, 171 underwent conversion from CsA to Tac (group I) and 533 remained on the CsA since transplantation (Group II). Time-dependent Cox regression and generalized estimating equations were used to account for sequential CNI exposure. NODAT and IFG occurred in 15.2% and 22.1% of group I subjects and 15.6% and 25.8% of group II subjects, respectively (p = 0.90 for NODAT and p = 0.38 for IFG). Accounting for equal follow-up time since conversion from CsA to Tac, the adjusted 5-year NODAT-free survival was 87.4% and 91.4% in group I and group II, respectively (p = 0.90). In conclusion, conversion to Tac, compared to continuous exposure to CsA, carries quantitatively similar risk of impaired glucose metabolism in KTRs in the late posttransplant period. | 18,786,231 |
Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm. | Controlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism. Forty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II. Compared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively. PSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction. | 18,786,263 |
Computational detection of significant variation in binding affinity across two sets of sequences with application to the analysis of replication origins in yeast. | In analyzing the stability of DNA replication origins in Saccharomyces cerevisiae we faced the question whether one set of sequences is significantly enriched in the number and/or the quality of the matches of a particular position weight matrix relative to another set. We present SADMAMA, a computational solution to a address this problem. SADMAMA implements two types of statistical tests to answer this question: one type is based on simplified models, while the other relies on bootstrapping, and as such might be preferable to users who are averse to such models. The bootstrap approach incorporates a novel "site-protected" resampling procedure which solves a problem we identify with naive resampling. SADMAMA's utility is demonstrated here by offering a plausible explanation to the differential ARS activity observed in our previous mcm1-1 mutant experiments 1, by suggesting the relevance of multiple weak ACS matches to efficient replication origin function in Saccharomyces cerevisiae, and by suggesting an explanation to the observed negative effect FKH2 has on chromatin silencing 2. SADMAMA is available for download from http://www.cs.cornell.edu/~keich/. | 18,786,274 |
[The potential role of high mobility group box 1 protein in immune dysfunction and its regulatory mechanism after major trauma]. | To investigate the potential effect of high mobility group box 1 protein (HMGB1) on host immune response and its molecular regulation mechanism as well as its interventional pathway following major burns/trauma. With both animal experiments and clinical investigation, serial studies were conducted to observe the effects of HMGB1 on changes in immune function of T lymphocytes, dendritic cells, and macrophages both in vivo and in vitro. It was found that thermal injury or trauma induced a delayed and persistent increase in HMGB1 expression as well as its release in various tissues. HMGB1 formation could markedly influence the cell-mediated immunity, including the changes in T lymphocytes, dendritic cells, and macrophages following major trauma or burns. These effects were closely related with dysfunction of various organs in the course of sepsis. These data proved that HMGB1 not only acts as a novel "late" inflammatory mediator but is also closely associated with immunosuppression after acute insults. HMGB1 might play an important role in inducing systemic inflammatory response together with host immunological dissonance, resulting in the development of septic complications. Intervention of HMGB1 expression and release presumably provides a potentially effective way to regulate both excessive inflammatory and immune response, thereby as a measure to improve the prognosis of severe sepsis secondary to major trauma. | 18,786,304 |
[The relationship between dysfunction of cell-mediated immunity and prognosis in severely burned patients]. | To investigate the relationship between dysfunction of cell-mediated immunity and prognosis in severely burned patients. Twenty-six patients with total burn surface area larger than 70% total body surface area (TBSA) were included in the present study, and they were divided into non-survival group (14 cases) and survival group (12 cases). Eleven healthy volunteers served as controls. The blood samples were collected on days 1, 3, 7, 14 postburn, the human leukocyte antigen-DR (HLA-DR) bound on CD14+ mononuclear cell surface of burned patients was quantified by flow cytometry (using monoclonal antibody, QuantiBRITE anti-HLA-DR PE/anti-monocyte PerCP-Cy5.5). The ability of T lymphocyte proliferation was determined by thiazolyl blue (MTT) method, and interleukin-2 (IL-2) release was measured by enzyme-linked immunosorbent assay (ELISA). Compared to the survival group, the T lymphocyte proliferative activity (0.739+/-0.299 vs. 0.320+/-0.237) and IL-2 release [(11.02+/-2.50) ng/L vs. (8.21+/-2.63) ng/L] in non-survival group were significantly decreased on postburn day 14 (P < 0.01 and P < 0.05). The expression of HLA-DR on CD14+ mononuclear cell surface was persistently decreased in non-survivors, while it markedly elevated in survivors after 14 days postburn (P < 0.01). The cellular immune function is consistently suppressed in severely burned patients. Sequential monitoring of T lymphocyte proliferation, IL-2 release, and the amount of HLA-DR on CD14+ mononuclear cell surface might be of clinical prognostic significance in patients with massive burn injury. | 18,786,305 |
Perspectives on the etiology of chronic rhinosinusitis: an immune barrier hypothesis. | Chronic rhinosinusitis (CRS) has been defined as persistent symptomatic inflammation of the nasal and sinus mucosa resulting from the interaction of multiple host and environmental factors. Recent studies have implicated Alternaria fungi or toxigenic Staphylococcus aureus as critical agents in CRS pathogenesis. The emphasis on environmental agents in CRS etiology has focused interest toward elimination of those agents as the prime mechanism of therapy. This viewpoint is in marked contrast to the current perspective on some other chronic inflammatory epithelial disorders that afflict the skin, lungs, and gut, wherein host factors are believed to predispose to disease expression in the presence of ubiquitous environmental agents. The current review evaluates CRS etiology from this perspective and considers that CRS develops, in part, as an outcome of a dysfunctional host response. Specifically, evidence from our laboratory and others will be reviewed indicating that CRS is associated with a failure of the mechanical and immunologic barriers across the nasal mucosa. The hypothesis would further propose that genetic and epigenetic variation predisposes susceptible individuals to barrier failure in the presence of environmental stress leading to CRS. From this unifying perspective, bacteria and fungi are seen as disease modifiers rather than primary etiologic agents. The goal is to place concepts of CRS pathophysiology in a framework consistent with a current understanding of chronic inflammation in general and epithelial disease in particular. | 18,786,300 |
How to implement incretin therapy. | The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines. This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM). This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM. | 18,786,341 |
[Not Available]. | Severe tooth wear is discussed from the perspective of appreciating the aetiologic background of the problem. A multifactorial basis is acknowledged for the extensively worn dentition and efforts to eliminate or minimize these underlying factors are important. The management of a case of severe incisal and occlusal wear can adopt different approaches. The author proposes the rationale and advantages for involving orthodontic preparation as part of the occlusal rehabilitation. | 18,786,347 |
Scent of a fly. | Sexual courtship is a highly ritualized behavior in many animals. Recent work in the vinegar fly, Drosophila melanogaster, has illuminated how the pheromone cis-vaccenyl acetate modulates sexual behavior in the fly. Chemosensory receptors and a sexually dimorphic circuit activated by this pheromone have been identified. This minireview highlights recent advances in the field of fly courtship. | 18,786,353 |
p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease. | The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders. | 18,786,355 |
Large-scale movement within the voltage-sensor paddle of a potassium channel-support for a helical-screw motion. | The size of the movement and the molecular identity of the moving parts of the voltage sensor of a voltage-gated ion channel are debated. In the helical-screw model, the positively charged fourth transmembrane segment S4 slides and rotates along negative counter charges in S2 and S3, while in the paddle model, S4 carries the extracellular part of S3 (S3b) as a cargo. Here, we show that S4 slides 16-26 A along S3b. We introduced pairs of cysteines in S4 and S3b of the Shaker K channel to make disulfide bonds. Residue 325 in S3b makes close and state-dependent contacts with a long stretch of residues in S4. A disulfide bond between 325 and 360 was formed in the closed state, while a bond between 325 and 366 was formed in the open state. These data are not compatible with the voltage-sensor paddle model, but support the helical-screw model. | 18,786,360 |
New insights into ancient seasonal life timers. | Organisms must adapt to seasonal changes in the environment and time their physiology accordingly. In vertebrates, the annual change in photoperiod is often critical for entraining the neuroendocrine pathways, which drive seasonal metabolic and reproductive cycles. These cycles depend on thyroid hormone (TH), reflecting its ancestral role in metabolic control. Recent studies reveal that--in mammals and birds--TH effects are mediated by the hypothalamus. Photoperiodic manipulations alter hypothalamic TH availability by regulating the expression of TH deiodinases (DIO). In non-mammalian vertebrates, light acts through extraretinal, 'deep brain' photoreceptors, and the eyes are not involved in seasonal photoperiodic responses. In mammals, extraretinal photoreceptors have been lost, and the nocturnal melatonin signal generated from the pineal gland has been co-opted to provide the photoperiodic message. Pineal function is phased to the light-dark cycle by retinal input, and photoperiodic changes in melatonin secretion control neuroendocrine pathway function. New evidence indicates that these comparatively divergent photosensensory mechanisms re-converge in the pars tuberalis of the pituitary, lying beneath the hypothalamus. In all vertebrates studied, the pars tuberalis secretes thyrotrophin in a light- or melatonin-sensitive manner, to act on neighbouring hypothalamic DIO expressing cells. Hence, an ancient and fundamentally conserved brain thyroid signalling system governs seasonal biology in vertebrates. | 18,786,385 |
Notch signaling specifies megakaryocyte development from hematopoietic stem cells. | In the hematopoietic system, Notch signaling specifies T cell lineage fate, in part through negative regulation of B cell and myeloid lineage development. However, we unexpectedly observed the development of megakaryocytes when using heterotypic cocultures of hematopoietic stem cells with OP9 cells expressing Delta-like1, but not with parental OP9 cells. This effect was abrogated by inhibition of Notch signaling either with gamma-secretase inhibitors or by expression of the dominant-negative Mastermind-like1. The importance of Notch signaling for megakaryopoietic development in vivo was confirmed by using mutant alleles that either activate or inhibit Notch signaling. These findings indicate that Notch is a positive regulator of megakaryopoiesis and plays a more complex role in cell-fate decisions among myeloid progenitors than previously appreciated. | 18,786,418 |
A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. | Current approaches to reprogram human somatic cells to pluripotent iPSCs utilize viral transduction of different combinations of transcription factors. These protocols are highly inefficient because only a small fraction of cells carry the appropriate number and stoichiometry of proviral insertions to initiate the reprogramming process. Here we have generated genetically homogeneous "secondary" somatic cells, which carry the reprogramming factors as defined doxycycline (DOX)-inducible transgenes. These cells were obtained by infecting fibroblasts with DOX-inducible lentiviruses, isolating "primary" iPSCs in the presence of the drug, and finally differentiating to "secondary" fibroblasts. When "secondary" fibroblast lines were cultured in the presence of DOX without further viral infection, up to 2% of the cells were reprogrammed to pluripotent "secondary" human iPSCs. This system will facilitate the characterization of the reprogramming process and provides a unique platform for genetic or chemical screens to enhance reprogramming or replace individual factors. | 18,786,421 |
Recurrent der(9;18) in essential thrombocythemia with JAK2 V617F is highly linked to myelofibrosis development. | We studied JAK2 mutational status, in combination with cytogenetic analysis in 54 patients with essential thrombocythemia (ET), and attempted to obtain greater insight into the correlation between clinicohematologic features and genetic abnormalities. We found that six ET patients developed myelofibrosis and four of them had JAK2 V617F mutation. It is noteworthy that three of the four ET patients with JAK2 V617F had add(18)(p11). In contrast, the remaining two ET patients who developed myelofibrosis had neither JAK2 V617F nor add(18)(p11). Moreover, none of the ET patients with JAK2 V617F and chromosome changes other than add(18)(p11) developed myelofibrosis. The current results indicate that add(18)(p11), possibly due to der(9;18), may contribute a link to myelofibrosis in JAK2 V617F-positive ET patients, while those with wild-type JAK2 may use another pathway toward myelofibrosis. | 18,786,436 |
Distinct karyotypes in three breast cancer cell lines --21PTCi, 21NTCi, and 21MT-1 --derived from the same patient and representing different stages of tumor progression. | Three breast carcinoma cell lines --21PTCi, 21NTCi, and 21MT-1 --all originating from a 36-year-old woman with metastatic breast cancer, have been characterized previously as stably representing different stages of progression: (nontumorigenic [21PTCi]; tumorigenic, nonmetastatic [21NTCi]; and tumorigenic, weakly metastatic [21MT-1]). These cell lines were investigated for cytogenetic characteristics using G-banding and spectral karyotyping. All three cell lines have multiple chromosome aberrations, but they differ in the types of rearrangements and breakpoints. 21PTCi cells have a modal number (mn) of 56, with 55 types of aberrations, including 16 numeric and 39 structural. 21NTCi cells have a mn of 56, with 70 types of aberrations, including 19 numerical and 51 structural. Finally, 21MT-1 cells have a mn of 54, with 43 types of aberrations, including 14 numerical and 29 structural. The most common rearrangements differ in each cell line [i.e., der(X)t(X;3), der(4)t(1;4), del(6q) and der(19)t(17;19)(q11.2;q13.4) in 21PTCi; der(4)t(1;4), der(12)t(12;15) and -16 in 21NTCi; and der(1)t(1;10), +5, der(6)t(6;7), der(11)t(11;13), -20, and der(20)t(20;21) in 21MT-1]. This cytogenetic result is consistent with previous findings in that the three cell lines represent different stages of tumor progression. We hypothesize that the cytogenetic changes in these cell lines may be related to their distinct biologic characteristics. These three cell lines, with their different karyotypes and biologic characteristics, provide a vital tool for further study of the genetic and epigenetic events involved in transitions between premalignant and malignant phenotypes. | 18,786,440 |
Adherence to hand hygiene in an Italian long-term care facility. | In an Italian long-term-care facility (LTCF), we observed a 17.5% adherence to hand hygiene (HH), as well as 47.5% rate of glove use. Performing a procedure at high risk for cross-transmission of germs was the factor most strongly associated with noncompliance (odds ratio = 13.3; 95% confidence interval = 6.2 to 28.8; P < .0001). No significant differences in compliance related to health care worker category were found. Adherence to HH in the LTCF was similar to that found in a rehabilitation medicine unit of an acute care hospital (15.8%) but significantly lower than that reported in an infectious disease unit (53.7%; P < .0001). Our findings indicate that compliance with HH is a similar problem in LTCFs as in acute care facilities. | 18,786,454 |
Protective effect of aspartate and glutamate on cardiac mitochondrial function during myocardial infarction in experimental rats. | The present study investigates the effect of aspartate and glutamate on mitochondrial function during myocardial infarction (MI) in wistar rats. Male albino wistar rats were pretreated with aspartate [100 mg(kgbody weight)(-1) day(-1)] or glutamate [100 mg(kg body weight)(-1) day(-1)] intraperitoneally for a period of 7 days. Following amino acid treatment, MI was induced in rats by subcutaneous injection of isoproterenol [200 mg(kg body weight)(-1) day(-1)] for 2 days at an interval of 24 h. Isoproterenol (ISO) induction resulting in significant (P<0.05) increase in the levels of cardiac mitochondrial lipid peroxidation with a decrease in reduced glutathione level. The activities of glutathione peroxidase and glutathione reductase were significantly (P<0.05) decreased by ISO. ISO-induction also caused significant (P<0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (malate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome-c-oxidase). ISO significantly (P<0.05) reduced the cytochrome contents, ATP production, ADP/O ratio and oxidation of succinate in state 3/state 4 whereas significantly (P<0.05) increased NADH oxidation. Pretreatment with aspartate or glutamate significantly (P<0.05) reduced the alterations induced by ISO and maintained normal mitochondrial function. The present findings reveal the protective effect of aspartate and glutamate on cardiac mitochondrial function in myocardial infarction-induced rats. | 18,786,522 |
Importance of the C-terminus of the human 5-HT3A receptor subunit. | Amongst the family members of Cys-loop LGICs, the atypical ability of the 5-HT3A subunit to form functional homomeric receptors allowed a direct investigation of the role of the C-terminus. Deletion of the three C-terminal amino acids (DeltaGln453-DeltaTyr454-DeltaAla455) from the h5-HT3A subunit prevented formation of a specific radioligand binding site as well as expression within the cell membrane. Removal of merely the C-terminal residue (DeltaAla455) reduced specific radioligand binding (to 4+/-1% relative to the wild-type; cells grown at 37 degrees C) and also cell membrane expression; these reductions were less evident when the DeltaAla455 expressing cells were grown at 27 degrees C (specific radioligand binding levels 27+/-5% relative to wild-type also grown at 27 degrees C). Mutation of the h5-HT3A C-terminal amino acid, alanine, for either glycine (Ala455Gly), valine (Ala455Val) or leucine (Ala455Leu) reduced specific radioligand binding levels by 24+/-23%, 32+/-12% and 88+/-1%, respectively; the latter mutant also displaying reduced membrane expression. In contrast, mutation to alanine of the two amino acids preceding the C-terminal alanine (Gln453Ala and Tyr454Ala) had no detrimental effects on specific radioligand binding or cell membrane expression levels. The present study demonstrates an important role for the C-terminus in the formation of the functional h5-HT3A receptor. The partial restoration of 5-HT3 receptor binding and cell membrane expression when cells expressing C-terminal mutant 5-HT3A subunits were grown at a lower temperature (27 degrees C) suggests that the C-terminus stabilises the 5-HT3 receptor allowing subunit folding and subsequent maturation. | 18,786,552 |
Indirubin-3'-oxime impairs mitochondrial oxidative phosphorylation and prevents mitochondrial permeability transition induction. | Indirubin, a red colored 3,2'-bisindole isomer, is a component of Indigo naturalis and is an active ingredient used in traditional Chinese medicine for the treatment of chronic diseases. The family of indirubin derivatives, such as indirubin-3'-oxime, has been suggested for various therapeutic indications. However, potential toxic interactions such as indirubin effects on mitochondrial bioenergetics are still unknown. This study evaluated the action of indirubin-3'-oxime on the function of isolated rat liver mitochondria contributing to a better understanding of the biochemical mechanisms underlying the multiple effects of indirubin. Indirubin-3'-oxime incubated with isolated rat liver mitochondria, at concentrations above 10microM, significantly depresses the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial membrane potential and in the phosphorylative cycle induced by ADP. Furthermore, indirubin-3'-oxime at up to 25microM stimulates the rate of state 4 respiration and inhibits state 3 respiration. The increased lag phase of repolarization was associated with a direct inhibition of the mitochondrial ATPase. Indirubin-3'-oxime significantly inhibited the activity of complex II and IV thus explaining the decreased FCCP-stimulated mitochondrial respiration. Mitochondria pre-incubated with indirubin-3'-oxime exhibits decreased susceptibility to calcium-induced mitochondrial permeability transition. This work shows for the first time multiple effects of indirubin-3'-oxime on mitochondrial bioenergetics thus indicating a potential mechanism for indirubin-3'-oxime effects on cell function. | 18,786,556 |
The yeast lysosome-like vacuole: endpoint and crossroads. | Fungal vacuoles are acidic organelles with degradative and storage capabilities that have many similarities to mammalian lysosomes and plant vacuoles. In the past several years, well-developed genetic, genomic, biochemical and cell biological tools in S. cerevisiae have provided fresh insights into vacuolar protein sorting, organelle acidification, ion homeostasis, autophagy, and stress-related functions of the vacuole, and these insights have often found parallels in mammalian lysosomes. This review provides a broad overview of the defining features and functions of S. cerevisiae vacuoles and compares these features to mammalian lysosomes. Recent research challenges the traditional view of vacuoles and lysosomes as simply the terminal compartment of biosynthetic and endocytic pathways (i.e. the "garbage dump" of the cell), and suggests instead that these compartments are unexpectedly dynamic and highly regulated. | 18,786,576 |
Impaired frontal synchronization of spontaneous magnetoencephalographic activity in patients with bipolar disorder. | Recent functional imaging studies demonstrated that brain exhibit coherent, synchronized activities during resting state and the dynamics may be impaired in various psychiatric illnesses. In order to investigate the change of neural dynamics in bipolar disorder, we used a new nonlinear measurement "similarity index" to analyze the magnetoencephalography (MEG) recordings and test the hypothesis that there are synchronization changes within different frequency bands in the frontal cortex of patients with bipolar disorder. Ten patients with bipolar I disorder during euthymic phase and ten normal controls underwent 2min eye-closed resting recording with a whole-head 306-channel MEG system. Eleven channels of MEG data from frontal area were selected for analysis. Synchronization level in the delta (2-4Hz), theta (4-8Hz), alpha (8-12Hz) and beta (12-24Hz) bands was calculated for each subject and compared across group. The results showed that significant dynamic changes in bipolar patients can be characterized by increased synchronization of slow frequency oscillations (delta) and decreased synchronization of fast frequency oscillations (beta). Furthermore, the positive correlation between beta synchronization level and preservative errors in Wisconcin card sorting task was found which would implicate the deficit of executive function in bipolar patients. Our findings indicate that analysis of spontaneous MEG recordings at resting state using nonlinear dynamic approaches may disclose the subtle regional changes of neural dynamics in BD. | 18,786,606 |
Calpastatin overexpression attenuates amyloid-beta-peptide toxicity in differentiated PC12 cells. | Amyloid beta peptide (Abeta) plays a major role in the pathogenesis of Alzheimer's disease (AD). Abeta is toxic to neurons, possibly through causing initial synaptic dysfunction and neuronal membrane dystrophy, promoted by increased cellular Ca(2+). Calpain (Ca(2+)-dependent protease) and caspase have been implicated in AD. Previously, we used calpain and caspase pharmacological inhibitors to study effects of Abeta25-35 (sAbeta) on neuronal-like differentiated PC12 cells. We reported that sAbeta-treated cells exhibited calpain activation and protein degradation (due to both calpain and caspase-8). We have now found that overexpression of the calpain specific inhibitor calpastatin in differentiated PC12 cells significantly inhibited the sAbeta-induced calpain activation and decreased the protease activity. Calpastatin overexpression inhibited the sAbeta-promoted degradation of fodrin, protein kinase Cepsilon, beta-catenin (membrane structural proteins and proteins involved in signal transduction pathways), and prevented the sAbeta-induced alteration of neurite structure (manifested by varicosities). Overexpression of calpastatin also inhibited Ca(2+)-promoted calpain activation and protein degradation; this is consistent with the notion that the Abeta-induced increase in calpain activity results from a rise in cellular Ca(2+), provided the calpastatin level is not so high as to strongly inhibit calpain. Carrying out transfection without selection allowed the comparison in the same culture of calpastatin-overexpressing with non-overexpressing cells. In cultures transfected with green fluorescent protein (GFP)-calpastatin plasmid, calpastatin overexpression (indicated by GFP-labeling) led to inhibition in sAbeta-induced membrane propidium iodide (PI) permeability, whereas non-transfected, GFP-unlabeled cells exhibited PI permeability. Overall, the results demonstrate that the effects of Abeta-toxicity studied here were attenuated to a large extent by calpastatin overexpression, indicating that the protease calpain is involved in Abeta-toxicity (obviating a primary, direct role for caspases). Increased expression of calpastatin and/or decrease in calpain may serve as one of the means for ameliorating some of the early symptoms of AD. | 18,786,620 |
Transfection activity of layer-by-layer plasmid DNA/poly(ethylenimine) films deposited on PLGA microparticles. | Layer-by-layer (LbL) assemblies of DNA and polycations on the surface of colloidal templates can be used for gene delivery. Plasmid DNA encoding for secreted alkaline phosphatase (SEAP) was used to deposit LbL films with poly(ethylenimine) (PEI) on the surface of polystyrene and poly(lactide-co-glycolide) microparticles. The formation of LBL films was confirmed by zeta potential analysis and fluorescence and atomic force microscopy techniques. The LbL particles were rapidly internalized in a dose-dependent manner by J774.1 murine macrophages. Transfection activity of the LbL particles was evaluated in J774.1 cells using three different doses (5, 10, 25 particle per cell). The levels of SEAP expression increased with increasing dose but were lower than transfection levels mediated by control PEI/DNA polyplexes at corresponding DNA doses. The LbL particles reported here present a promising platform for delivery of DNA to phagocytic cells. | 18,786,622 |
Microfluidic-based enzymatic on-chip labeling of miRNAs. | Small noncoding RNAs (sncRNAs) have moved from oddity to recognized important players in gene regulation. Next generation sequencing approaches discover more and more such molecules from a variety of different groups, but flexible tools translating this sequence information into affordable high-throughput assays are missing. Here we describe a microfluidic primer extension assay (MPEA) for the detection of sncRNAs on highly flexible microfluidic microarrays which combines several beneficial parameters: it can effortless incorporate any new sequence information; it is sensitive enough to work with as little as 20ng of total RNA and has a high level of specificity owing to a combination of a conventional hybridization assay and an enzymatic elongation step. Importantly, no labeling step is needed before hybridization and - because of its high sensitivity - no amplification is required. Both aspects ensure that no bias is introduced by such processes. Although the assay is exemplified with miRNAs, the flexibility of the technology platform allows the analysis of any type of sncRNA, such as piRNAs. | 18,786,664 |
In situ fabrication of silver nanoarrays in hyaluronan/PDDA layer-by-layer assembled structure. | We present a simple in situ method to fabricate silver (Ag) nanoparticle arrays in a layer-by-layer (LBL) assembled hyaluronan (HA)/poly(dimethyldiallylammonium chloride) (PDDA) multilayer structure, in which the LBL multilayered film is constructed by electrostatic attraction between positively charged PDDA and negatively charged HA, followed by in situ synthesis of embedded Ag nanoparticle arrays in the LBL "nanoreactors," where the abundant negatively charged carboxyl groups of HA bind and further reduce Ag(+) ions under UV-irradiating. The arrays morphology is highly dependent on the number of bilayers, and the surface density of nanoparticles in the arrays can be simply tailored by the number of irradiation/drying cycles during fabrication. The embedded Ag nanoparticle arrays possess good stability for localized surface plasmon resonance (SPR) absorption spectrum-based biosensors and superior antimicrobial capability. These render great potentials for the films in both biosensing and antimicrobial applications. | 18,786,677 |
Influence of pharmaceutical residues on the structure of activated sludge bacterial communities in wastewater treatment bioreactors. | Concern is growing over contamination of the environment with pharmaceuticals because of their widespread use and incomplete removal during wastewater treatment, where microorganisms drive the key processes. The influence of pharmaceuticals on bacterial community structure in activated sludge was assessed in small-scale wastewater treatment bioreactors containing different concentrations (5, 50, 200 and 500microgL(-1)) of several commonly used pharmaceuticals (ibuprofen, naproxen, ketoprofen, diclofenac and clofibric acid). T-RFLP analyses of the bacterial 16S rRNA genes indicated a minor but consistent shift in the bacterial community structure in the bioreactor R50 supplied with pharmaceuticals at a concentration of 50microgL(-1), compared to the control reactor R0, which was operated without addition of pharmaceuticals. In the reactors operated with higher concentrations of pharmaceuticals, a greater structural divergence was observed. Bacterial community composition was further investigated by preparation of two clone libraries of bacterial 16S rRNA genes from reactors R0 and R50. Most clones in both libraries belonged to the Betaproteobacteria, among which Thauera, Sphaerotilus, Ideonella and Acidovorax-related spp. dominated. Nitrite-oxidizing bacteria of the genus Nitrospira sp., which are key organisms for the second stage of nitrification in wastewater treatment plants, were found only in the clone library of the reactor without pharmaceuticals. In addition, diversity indices were calculated for the two clone libraries, indicating a reduced diversity of activated sludge bacterial community in the reactor supplied with 50microgL(-1) of each of selected pharmaceuticals. | 18,786,690 |
Changes in subpopulations of boar sperm defined according to viability and plasma and acrosome membrane status observed during storage at 15 degrees C. | Four boar ejaculates were preserved for 42d at 15 degrees C to examine the changes produced in the quality of sperm membranes according to their response to a combined short hypoosmotic swelling test (sHOST) plus viability test designated the sHV test. Every 1 or 2d, a sample from each ejaculate preserved in long-term extender was subjected to sperm motility determination and the sHV test. Through simultaneous examination by phase contrast and fluorescence microscopy, three subpopulations of sperm were identified according to their response to sHOST challenge and their viability status. In the subpopulations scoring positive in the sHOST, a further four sperm subpopulations were defined according to their viability and acrosome status. All the sperm subpopulations differed in terms of changes in their proportions produced during the course of preservation and individual differences among ejaculates were detected in terms of relationships shown among subpopulations. The combined sHOST/viability test was able to identify sperm subpopulations with the strongest plasma and acrosome membranes as well as a subpopulation of sperm that had undergone a true acrosome reaction. | 18,786,721 |
Clinical correlates of depersonalization symptoms in patients with bipolar disorder. | Prevalence and clinical correlates of dissociative symptoms in general, and depersonalization (DP) in particular, in patients with mood disorders have received limited attention in the literature. Nevertheless, the identification of these symptoms may have important implications in terms of a better definition of clinical endophenotypes. Thus, this study aimed at investigating frequency and clinical correlates of dissociative symptoms, with special attention to DP symptoms, in patients with bipolar disorder (BD) looking specifically at differences between BD-I and BD-II and the comorbidity with panic disorder. The study sample included 91 adult patients with BD (BD-I=43; BD-II=48) assessed with the Semi-structured Clinical Interview for Temperament (TEMPS-I), the Dissociative Experiences Scale (DES) and the Structured Clinical Interview for Depersonalization-Derealization Spectrum (SCI-DER). There was no difference in lifetime dissociative experiences or DP symptoms between BD-I and BD-II patients. There was no difference in relation to temperament characteristics. Lifetime DP symptoms, as assessed with the SCI-DER, were associated to an early onset of the BD (beta=-0.436, t=-4.572, p<0.001). Derealization symptoms correlated with panic disorder comorbidity (OR=1.22; 95%CI=1.03-1.46, Wald=5.177, p=0.023). Our study suggests that lifetime DP symptoms are correlated with an early onset of the BD and derealization symptoms with panic disorder comorbidity, bearing the opportunity to identify patients with a specific profile for a better clinical and neurobiological definition. | 18,786,726 |
Expression of neurotrophin receptors by proliferating glia in postischemic hippocampal CA1 sector of adult monkeys. | Transient global cerebral ischemia elicits a nearly total neuronal cell death in the hippocampal CA1 sector, accompanied by a marked microglial and astroglial proliferation. The molecular mechanisms regulating the postischemic glial reaction in the primate brain remain obscure. Here we present in situ evidence that proliferating postischemic microglia in adult monkey CA1 sector express the neurotrophin receptor TrkA, while activated astrocytes were labeled for the TrkA ligand nerve growth factor (NGF) and the tyrosine kinase TrkB, a receptor for brain-derived neurotrophic factor (BDNF). These results implicate NGF and BDNF as regulators of postischemic glial proliferation in adult primate hippocampus. | 18,786,730 |
Rat area postrema microglial cells act as sensors for the toll-like receptor-4 agonist lipopolysaccharide. | The area postrema (AP) represents the sensory circumventricular organ lacking endothelial blood-brain barrier function in direct vicinity to the 4th cerebral ventricle. Administration of lipopolysaccharide (LPS), as opposed to muramyldipeptide (MDP) or fibroblast-stimulating lipopeptide-1 (FSL-1), caused fast transient rises in intracellular calcium concentrations in 10-12% of the microglial cells investigated in a primary microculture of the rat AP,with limited responses of neurons, astrocytes and oligodendrocytes. In addition, a marked release of the pro-inflammatory cytokines TNF-alpha and IL-6 was determined in LPS-treated AP microcultures. Pre-incubation of AP microcultures with LPS for 18 h suppressed LPS-induced calcium signaling and attenuated cytokine secretion. Evidently, the AP can act as a sensor for circulating LPS and has the capacity to develop endotoxin-tolerance. | 18,786,731 |
Attenuated metabolic effect of waist measurement in Japanese female patients with type 2 diabetes mellitus. | Waist circumference (WC) was measured in 200 Japanese patients with type 2 diabetes mellitus (T2DM: male 106, female 94, mean age 61 years old) who had been admitted in our hospital, and relationship with various risk factors to predict future cardiovascular disease (CVD) was analyzed. There was a positive and statistically significant trend in WC levels with an increasing number of CVD risk factors in male patients, whereas no significant trend of WC was observed in female patients. The receiver operator characteristic (ROC) curve for WC to predict the presence of two or more risk factors of CVD depicted greater area under the curve in male patients (0.732) than that in female patients (0.571). Apart from positive correlation with fasting serum C-peptide (S-CPR) and log-transformed high-sensitivity C-reactive protein (log HS-CRP) in both genders, WC was positively correlated with log-transformed triglyceride (log TG), systolic and diastolic blood pressure (SBP and DBP) and negatively with HDL-cholesterol (HDL-C) in male patients, whereas it was negatively correlated with HbA1c and fasting plasma glucose (FPG) in female patients. The change of WC after administration (DeltaWC) was correlated with DeltaS-CPR, DeltaLDL-C, DeltaSBP and DeltaDBP in male patients, while no relationship was observed in female patients. In conclusion, WC is a reliable marker to predict future CVD events at least in Japanese male, but not female patients with T2DM. | 18,786,739 |
Widespread conservation of genetic redundancy during a billion years of eukaryotic evolution. | Genetic redundancy means that two genes can perform the same function. Using a comprehensive phylogenetic analysis, we show here in both Saccharomyces cerevisiae and Caenorhabditis elegans that genetic redundancy is not just a transient consequence of gene duplication, but is often an evolutionary stable state. In multiple examples, genes have retained redundant functions since the divergence of the animal, plant and fungi kingdoms over a billion years ago. The stable conservation of genetic redundancy contrasts with the more rapid evolution of genetic interactions between unrelated genes and can be explained by theoretical models including a 'piggyback' mechanism in which overlapping redundant functions are co-selected with nonredundant ones. | 18,786,741 |
Randomized placebo-controlled trial assessing a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on plasma asymmetric dimethylarginine concentration in mild to moderate CKD. | Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study. Secondary analysis of a randomized double-blind placebo-controlled trial. 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2) (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands. The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin B(12), 1 mg/d, all in 1 tablet) were added and continued for another year. The control group received matching placebos. Plasma ADMA levels. 36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 +/- 0.07 (SD) and 1.14 +/- 0.46 mumol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (beta = -0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02). The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low. Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention. | 18,786,751 |
Dentin tubule numerical density variations below the CEJ. | To evaluate dentin tubule numerical density variations below the CEJ. Three human non-carious permanent canines were sectioned parallel to the CEJ to obtain dentin disks 1mm thick whose surfaces were 1mm and 2mm below the CEJ. Each disk was sectioned into quarters resulting in four segment locations: facial, lingual, mesial, and distal. The outer (PDL side) and inner (pulp side) surfaces of the specimens were shaped to expose dentin with SiC papers and polished. Numerical tubule density was determined from SEM images. All data were statistically analyzed using a three-way ANOVA. The dentin tubule density (number/mm(2)) ranged from 13,700 to 32,300. Dentin tubule density was relatively uniform at 1mm and 2mm below the CEJ and increased by a factor of about two from the outer to the inner surface, which was significantly different (P<0.0001). The tubule density variations at the cervical root did not present marked. | 18,786,756 |
The effect of mifepristone on apoptosis and caspase-3 activation in human ovarian luteinized granulosa cells. | To investigate the effect of mifepristone, an oral contraceptive, on apoptosis in human ovarian luteinized granulosa cells. Human ovarian luteinized granulosa cells were treated in vitro with 1.25, 2.5, 5.0, 10.0, or 20.0 microM of mifepristone. Nuclear morphology, apoptosis ratio, and level of caspase-3 expression were determined with immunofluorescence microscopy, the terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay, and flow cytometry. We found that mifepristone-treated cells contained single condensed chromatin with multiple nuclear fragments, which is morphologic evidence of apoptosis. A significant difference was observed in the TUNEL assay between mifepristone-treated cells and control cells (P<0.05). Consistent with the results of the TUNEL assay, the fluorescence intensity of caspase-3 in drug-treated cells was also significantly different (P<0.05) from control cells; specifically, the difference between cells treated with different doses of drugs was much smaller and negligible. From these results, we propose that mifepristone induces human ovarian luteinized granulosa cells to undergo apoptosis by activating caspase-3. | 18,786,757 |
Interaction of malachite green with bovine serum albumin: determination of the binding mechanism and binding site by spectroscopic methods. | The interaction between malachite green (MG) and bovine serum albumin (BSA) under simulative physiological conditions was investigated by the methods of fluorescence spectroscopy, UV-vis absorption and circular dichroism (CD) spectroscopy. Fluorescence data showed that the fluorescence quenching of BSA by MG was the result of the formation of the MG-BSA complex. According to the modified Stern-Volmer equation, the effective quenching constants (K(a)) between MG and BSA at four different temperatures were obtained to be 3.734 x 10(4), 3.264 x 10(4), 2.718 x 10(4), and 2.164 x 10(4)L mol(-1), respectively. The enthalpy change (Delta H) and entropy change (DeltaS) were calculated to be -27.25 kJ mol(-1) and -11.23 J mol(-1)K(-1), indicating that van der Waals force and hydrogen bonds were the dominant intermolecular force in stabilizing the complex. Site marker competitive experiments indicated that the binding of MG to BSA primarily took place in sub-domain IIA. The binding distance (r) between MG and the tryptophan residue of BSA was obtained to be 4.79 nm according to Förster theory of non-radioactive energy transfer. The conformational investigation showed that the presence of MG decreased the alpha-helical content of BSA (from 62.6% to 55.6%) and induced the slight unfolding of the polypeptides of protein, which confirmed some micro-environmental and conformational changes of BSA molecules. | 18,786,760 |
The year in burns 2007. | In the year 2007, approximately 1000 original burn research articles were published in scientific journals using the English language. This article reviews approximately 90 of these which were deemed by the author to be the most important in terms of clinical burn care. Relevant topics include epidemiology, wound characterisation, critical care physiology, inhalation injury, infection, metabolism and nutrition, psychological considerations, pain management, rehabilitation, and burn reconstruction. Each selected article is mentioned briefly with editorial comment. | 18,786,767 |
Endoplasmic reticulum stress in beta cells: latent mechanism of secondary sulfonylurea failure in type 2 diabetes? | Sulfonylureas, by stimulating beta cell to secrete insulin, are still largely used for treatment of type 2 diabetic patients. More recently concern has been raised with respect to possible adverse effects associated with the use of these agents, like favoring beta cell apoptosis and beta cell exhaustion, which is believed as the reason for high rate secondary sulfonylurea failure. Endoplasmic reticulum (ER) stress often occurred when load of client protein exceed the folding capacity in secretory cell. Here, we hypothesize that overstimulation by chronic use of sulfonylureas could probably leads to ER stress and finally apoptosis in beta cell, which might be the latent mechanism for secondary sulfonylurea failure. | 18,786,775 |
Rhinocerebral Mucormycosis: consideration of prognostic factors and treatment modality. | Rhinocerebral mucormycosis is rare, rapidly progressive, potentially life-threatening disease, and it usually occurs in immunocompromised patients. We present our clinical experience with 12 cases and we attempt to identify the prognostic features and proper treatment protocols. All the cases of mucormycosis were proven by histology or culture. The prognosis was analyzed according to the predisposing factors, including underlying disease, extent of disease and surgical intervention. The overall mortality rate in our series was 33.3%. 7 of the 10 operated patients recovered, while 1 of the 2 non-operated patients expired. The associated conditions included diabetes mellitus (n=9) and hematological disease (n=3). A poor prognosis was primarily related with uncontrolled underlying disease. Other associated prognostic factors were the extent of disease including orbital or intracranial extension. Surgical debridement is essential for a good prognosis, but timely intervention and complete aggressive debridement are not always needed in all patients. The patient who had slowly progressive disease also survived after conventional medical management and limited surgical debridement, including orbital preservation. Control of the underlying predisposing illness along with prompt parenteral administration of amphotericin B and aggressive surgical debridement remain the essential treatments even today. Contrary to this, as described in this study, for the patients with slowly progressive disease, the aggressive surgical debridement is spared, and a successful result may be obtained with the conventional management, including medical treatment and timely limited surgical intervention. | 18,786,790 |
Pattern recognition system for the discrimination of multiple sclerosis from cerebral microangiopathy lesions based on texture analysis of magnetic resonance images. | In this study, a pattern recognition system has been developed for the discrimination of multiple sclerosis (MS) from cerebral microangiopathy (CM) lesions based on computer-assisted texture analysis of magnetic resonance images. Twenty-three textural features were calculated from MS and CM regions of interest, delineated by experienced radiologists on fluid attenuated inversion recovery images and obtained from 11 patients diagnosed with clinically definite MS and from 18 patients diagnosed with clinically definite CM. The probabilistic neural network classifier was used to construct the proposed pattern recognition system and the generalization of the system to unseen data was evaluated using an external cross validation process. According to the findings of the present study, statistically significant differences exist in the values of the textural features between CM and MS: MS regions were darker, of higher contrast, less homogeneous and rougher as compared to CM. | 18,786,795 |
[What should be known for the introduction of an HPV vaccine?]. | Genital human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. Two HPV vaccines are now available in many countries: (i) the first vaccine is quadrivalent and indicated in the prevention of CIN 2/3, cervical cancers, VIN 2/3, VaIN 2/3 and genital warts associated with the HPV types 6, 11, 16 and 18, (ii) the second vaccine is bivalent and indicated in the prevention of CIN 2+ and cervical cancers associated with the HPV types 16 and 18. To critically review all epidemiological aspects of the HPV infection and its relation with preneoplasic lesions of the cervix and cervical cancer to assist the relevant public health authorities to make plans for the introduction of HPV vaccines that have been recently commercialized. Only articles published in English in peer reviewed journals have been selected in Date base PubMed (National Library of Medicine - National Institutes of Health) with Keywords HPV, risk factor, cervical cancer, CIN2/3, incidence, prevalence, transmission, prevention, genital cancer, HPV vaccines, screening. A critical review of most papers published during the last 10 years was made. The topics covered included: diseases caused by HPV, prevalence, incidence and transmission of HPV, risk factors for the acquisition of HPV, natural history of HPV infection, risk factors determining the progression from HPV to cancer, protective factors blocking the progression from infection to cancer (screening) and primary prevention of HPV by vaccines and other methods. The information was interpreted and summarized. It was concluded that HPV infection is one of the most common sexually transmitted infections, that it is the necessary cause of cervical cancer and the cause of other genital cancers and cancers of the upper aerodigestive tract. Fortunately most infections regress, but those infections that persist are the ones leading to cancer. Primary prevention by the introduction of prophylactic vaccines is the ideal means of preventing cervical cancer and other cancers associated to HPV. This review is to my knowledge, the most comprehensive and up-to date review to be published in French on HPV epidemiology and related diseases. It will be of great value to educate medical and paramedical personnel on HPV infection and associated diseases and it will be of great help to public health authorities and decision makers when they have to evaluate the convenience of introducing HPV vaccination in a given population. | 18,786,806 |
A theory-based cross-sectional survey demonstrated the important role of awareness in guideline implementation. | To assess physiotherapists' adherence to the Dutch guidelines for nonspecific low back pain, the motivational determinants related to guideline adherence, and the role of physiotherapists' awareness of their performance in this respect. This was a cross-sectional survey among a random sample of 1,500 private practice physiotherapists in the Netherlands. The actual guideline adherence was measured by means of validated clinical vignettes and self-reported adherence by asking the physiotherapists to report their own level of adherence. The assessment of motivational determinants was based on a theoretical framework. The response rate was 31.5% (N=472). The average guideline adherence rate was 50.4% (SD=16.8). Only 38.5% of the physiotherapists had realistic perceptions of their personal performance. Awareness levels seriously interfered with the relationship between motivational determinants and actual guideline adherence. Actual adherence was mainly related to the perceived relative advantages and awareness of adherence to the perceived social norm. The moderating role of awareness in this study confirms the view that motivational determinants of a particular behavior can only be accurately assessed if people hold realistic perceptions of that behavior. Our approach illustrates the added value of a theory-based approach in guideline implementation studies. | 18,786,808 |
Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole. | We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene. In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n=14; A1A2+A2A2, n=76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured. Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups. The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole. | 18,786,813 |
High-flexion implants in primary total knee arthroplasty: a meta-analysis. | We asked whether a high-flexion design implant improves patient functional outcomes or range of motion (ROM) after primary knee arthroplasty. We searched the major medical databases for randomized trials and comparison observational studies comparing high-flexion and conventional knee implants. After testing for publication bias and heterogeneity, the data were aggregated by random effect modeling. We estimated the weighted mean differences of functional outcomes scores and ROM with 95% confidence intervals. Six studies met our inclusion criteria for review. We found no evidence of publication bias. The pooled mean difference for KSS scores was 0.144 (95% CI: -0.018 to 0.306), p=0.081. The pooled mean difference for the mean changes in ROM was 0.404 (95% CI: 0.139 to 0.669), p=0.003. High-flexion implant design improves overall ROM as compared to traditional implants but offers no clinical advantage over traditional implant designs in primary knee arthroplasty. | 18,786,829 |
Soft and hard tissue changes after bimaxillary surgery in Turkish female Class III patients. | Treatment of severe Class III malocclusion frequently requires a combination of orthodontics and orthognathic surgical procedures. The aims of this retrospective study were to assess the results of bimaxillary surgery on Turkish female subjects presenting with Class III malocclusions and to evaluate the correlation between soft and hard tissue changes. The sample consisted of 44 Turkish female Class III patients (mean age was 28.3+/-3.7 years) treated with bilateral sagittal split osteotomy and Le Fort I advancement with maxillary impaction. Lateral cephalograms were taken immediately before and 2.6+/-0.7 years after bimaxillary surgery. Paired t-test, Pearson correlation test and linear regression analysis procedures were used to assess the degree of correlation in terms of soft to hard tissue changes between the two cephalograms. All subjects presented with a presurgical concave profile. Maxillary advancement and impaction combined with mandibular setback surgery corrected the facial concavity and the improvement of horizontal and vertical positions. The lengths of the upper and lower lips and the horizontal position of the soft tissue pogonion were improved. The decrease in facial convexity angle was correlated with the increases in SNA angle and N-A distance. The significant increase in labiomental fold depth was significantly correlated with the significant decreases in N-ANS and ANS-Gn distances. The protrusion of the upper lip was correlated with the increases in SNA angle and N-A distance and also with the decrease in SNB angle. The retrusion of the lower lip was correlated with the decrease in N-B distance. The decrease in Sn to A distance was correlated with the increases in SNA, ANB and NAPg angles and N-A distance and also with the decrease in ANS-Gn distance. The increase in Pg' to Pg distance was correlated with the increases in SNA, ANB, NAPg angles and N-A distance. The increase in Si to B distance was correlated with the increases in SNA angle and N-A distance and also with the decreases in N-ANS and ANS-Gn distances. The decrease in Ls to U1 distance was correlated with the increases in SNA and ANB angles and with the increase in N-A distance and with the decreases in N-B and N-Pg distances. The decrease in Li to L1 distance was correlated with the increase in N-A distance. The elongation of the upper lip was correlated with the decrease in ANS-Gn distance. The increase in nasolabial angle was correlated with the decrease in ANS-Gn distance. Maxillary and mandibular soft and hard tissue movements showed significant correlations in horizontal and vertical directions 2.6+/-0.7 years after bimaxillary surgery. | 18,786,833 |
Prevalence of Rickettsia species antibodies and Rickettsia species DNA in the blood of cats with and without fever. | Rickettsia species antibodies have been detected in some cats but it is unknown whether infected cats develop clinical signs. The prevalence of Rickettsia species deoxyribonucleic acid (DNA) in blood from clinically ill cats has not been determined. The objective of this study was to determine if cats with fever (body temperature >or=102.5 degrees F [39.2 degrees C]) were more likely to have evidence of rickettsial infection than healthy, age-matched, control cats with a body temperature<102.5 degrees F. Rickettsia species polymerase chain reaction (PCR) assays were performed to detect rickettsial DNA extracted from blood (71 paired samples), indirect immunofluorescence assays (IFA) were performed to detect serum antibodies against Rickettsia felis (90 paired samples) and Rickettsia rickettsii (91 paired samples), and the results between pairs were compared. All samples were negative for Rickettsia species DNA. More cats with fever were seropositive for R felis or R rickettsii than control cats, but results were not statistically significant. Results of this pilot study failed to show an association between Rickettsia species DNA or Rickettsia species antibodies and fever. | 18,786,845 |
A new family of Ru(II) polypyridyl complexes containing open-chain crown ether for Mg2+ and Ca2+ probing. | Six polypyridyl bridging ligands BL(1-6) containing open-chain crown ether, where BL(1-3) formed by the condensation of 4,5-diazafluoren-9-hydrazine with 1,7-bis-(4-formylphenyl)-1,4,7-trioxaheptane, 1,10-bis-(4-formylphenyl)-1,4,7,10-tetraoxadecane, and 1,13-bis-(4-formylphenyl)-1,4,7,10,13-pentaoxatridecane, respectively, BL(4-6) formed by the reaction of 9-(4-hydroxy)phenylimino-4,5-diazafluorene with diethylene glycol di-p-tosylate, triethylene glycol di-p-tosylate, and tetraethylene glycol di-p-tosylate, respectively, have been synthesized. Reaction of Ru(bpy)(2)Cl(2).2H(2)O with BL(1-6), respectively, afforded six bimetallic complexes [(bpy)(2)RuBL(1-6)Ru(bpy)(2)](4+) as PF(6)(-) salts. Cyclic voltammetry of these complexes is consistent with one Ru(II)-centered oxidation around 1.32V and three ligand-centered reductions. These complexes show metal-to-ligand charge transfer absorption at 413-444 nm and emission at 570 nm. Binding behavior of complexes with alkali and alkaline-earth metal ions are investigated by UV-vis absorption, fluorescence, and cyclic voltammetry. Addition of alkali and alkaline-earth metal ions to the solution of [(bpy)(2)RuBL(1-6)Ru(bpy)(2)](PF(6))(4) all result in a progressive quenching of fluorescence, a hyperchromic effect of UV-vis absorption, and a progressive cathodal shift of Ru(II)-centered E(1/2). Ru-BL(2) and Ru-BL(5) show the highest binding ability toward Mg(2+) among the five cations examined while Ru-BL(3) and Ru-BL(6) exhibit good selective recognition ability to Ca(2+). | 18,786,850 |
The unintended consequences of computerized provider order entry: findings from a mixed methods exploration. | To describe the foci, activities, methods, and results of a 4-year research project identifying the unintended consequences of computerized provider order entry (CPOE). Using a mixed methods approach, we identified and categorized into nine types 380 examples of the unintended consequences of CPOE gleaned from fieldwork data and a conference of experts. We then conducted a national survey in the U.S.A. to discover how hospitals with varying levels of infusion, a measure of CPOE sophistication, recognize and deal with unintended consequences. The research team, with assistance from experts, identified strategies for managing the nine types of unintended adverse consequences and developed and disseminated tools for CPOE implementers to help in addressing these consequences. Hospitals reported that levels of infusion are quite high and that these types of unintended consequences are common. Strategies for avoiding or managing the unintended consequences are similar to best practices for CPOE success published in the literature. Development of a taxonomy of types of unintended adverse consequences of CPOE using qualitative methods allowed us to craft a national survey and discover how widespread these consequences are. Using mixed methods, we were able to structure an approach for addressing the skillful management of unintended consequences as well. | 18,786,852 |
Links between eye movement preparation and the attentional processing of tactile events: an event-related brain potential study. | We investigated whether the covert preparation of saccadic eye movements results in spatially specific modulations of somatosensory processing. ERPs were recorded in a spatial cueing experiment where auditory cues preceded tactile stimuli delivered to the left or right hand. In the Saccade task, cues signalled that an eye movement towards the left or right hand had to be prepared. In the Covert Attention task, cues signalled the direction of a covert shift of tactile attention. A lateralized component previously observed during cued shifts of spatial attention (ADAN) was elicited in the cue-target interval in both tasks. The somatosensory N140 component was enhanced for tactile stimuli presented to the hand on the cued side. This modulation was present not just in the Covert Attention task, but also in the Saccade task. Longer-latency effects of spatial cueing were only present in the Covert Attention task. Covert shifts of attention and saccade preparation have similar effects on early stages of tactile processing, suggesting that both are mediated by overlapping control processes. These findings support the premotor theory of attention by demonstrating that the programming of eye movements has spatially selective effects on somatosensory processing. | 18,786,857 |
Candidate gene polymorphisms and the 9p21 locus in acute coronary syndromes. | It is now widely accepted that the classic environmental risk factors for atherosclerosis only partly explain the incidence of coronary artery disease and the development of acute coronary syndromes. Therefore, genetic factors that vary among human populations seem to be involved in the clinical manifestations of such patients. Substantial data suggest that a significant proportion of genetic polymorphisms involved in endothelial function, inflammation, lipid metabolism, thrombosis and fibrinolysis are often present in patients with acute coronary syndromes. In particular, a common variant on chromosome 9p21 was recently identified to affect the risk of myocardial infarction. Here, we review the progress of candidate gene studies and genome-wide association studies in identifying the genetic bases of complex cardiovascular diseases such as acute coronary syndromes. | 18,786,860 |
Inverse coupling between respiratory and cardiac oscillators in a life-threatening event in a neonate. | The authors report the case of a baby boy born at a gestational age of 32 weeks who experienced a life-threatening event triggered by vagal overactivity, associated with a transient phase of inverse coupling with a 1:1 phase ratio between ECG and respiration, resulting in respiratory arrest. This case report highlights the vital importance of coupling between cardiac and respiratory oscillators, especially in premature infants or neonates. | 18,786,867 |
Longitudinal changes in quality of life and costs in long-term survivors of tumors of the oropharynx treated with brachytherapy or surgery. | Based on earlier studies we were interested in finding out if longitudinal assessment of quality of life (QoL) and costs in long-term survivors of oropharyngeal cancers treated with external beam radiation therapy and brachytherapy (BT) or surgery and postoperative radiotherapy showed a change in QoL over the years. Besides, we were curious to know how much the costs per life year and the QALY would be for this patient group. Performance status scales: eating in public, understandability of speech, normalcy of diet, xerostomia and ability to swallow were determined in 2003 and 2005. In 2005, the responses to EORTC QLQ-C30, EORTC H&N35, and the Euroqol questionnaire were also measured. Costs and quality-adjusted life years (QALYs) were calculated. Eating in public, understandability of speech, and normalcy of diet significantly differed in favor of BT. Surgical patients experienced more speech, teeth, and mouth-opening problems. Mean costs and QALYs for BT were 16,112 euros and 56,060 euros and for surgery 26,590 euros and 93,275 euros, respectively. QoL scores don't change over time. Due to the number of admission days, surgery is more costly. Difference in costs for QALYs in favor of BT was observed. | 18,786,864 |
[Non-verbal communication in Alzheimer's disease]. | This review underlines the importance of non-verbal communication in Alzheimer's disease. A social psychological perspective of communication is privileged. Non-verbal behaviors such as looks, head nods, hand gestures, body posture or facial expression provide a lot of information about interpersonal attitudes, behavioral intentions, and emotional experiences. Therefore they play an important role in the regulation of interaction between individuals. Non-verbal communication is effective in Alzheimer's disease even in the late stages. Patients still produce non-verbal signals and are responsive to others. Nevertheless, few studies have been devoted to the social factors influencing the non-verbal exchange. Misidentification and misinterpretation of behaviors may have negative consequences for the patients. Thus, improving the comprehension of and the response to non-verbal behavior would increase first the quality of the interaction, then the physical and psychological well-being of patients and that of caregivers. The role of non-verbal behavior in social interactions should be approached from an integrative and functional point of view. | 18,786,877 |
Psychiatriform disorders: psychiatric analogues of somatoform disorders. | Somatoform disorders can be understood to mimic supposedly more 'legitimate' physical disorders. To the extent that mental disorders are now also often considered legitimate, might clinicians expect to encounter the psychiatric equivalent of somatoform disorders, 'psychiatriform disorders'? The relevant literature on somatoform disorders is reviewed in light of the tendency for mental and physical symptoms to co-occur. Illness attribution and behaviour may explain some of the recent rise in the prevalence of mental disorder. Hypotheses regarding the cause and nature of somatoform disorders are applied to their proposed psychiatric equivalent. Despite lack of current recognition, there is a strong theoretical basis for the existence of psychiatriform disorders. Psychiatriform disorders can be expected to have similar causes, comorbidity, and response to treatment, as somatoform disorders. A variety of cultural forces may be contributing to a rise in prevalence. As with somatoform disorders, psychiatriform disorders present problems in their distinction from conscious fabrication and from the ;legitimate' disorders they mimic. Given their likely prevalence and associated impairments, psychiatriform disorders warrant further examination, despite the methodological difficulties this presents. | 18,786,901 |
The relationship between staff members' working conditions and patients' perceptions of the treatment environment. | The psychosocial climate of inpatient units has proved to be related to both patient satisfaction and outcome. The aims of the study were twofold: to study the relationship between patient and staff satisfaction, and to study the relationship between the patients' perception of the treatment environment and the perceived working conditions of the staff. A total of 129 different patients completed the Ward Atmosphere Scale (WAS) and a General Satisfaction Index (GSI) at 11 time points between 1981 and 2000. Staff members completed the Working Environment Scale-10 (WES-10) and the GSI. Z-scores were calculated to describe the fluctuations in the WAS, WES-10 and the GSI subscale scores. The study revealed a strong correlation between patient satisfaction and staff satisfaction. Staff satisfaction correlated significantly with the WAS subscales of Practical orientation and Staff control. Furthermore, the study revealed a significant correlation between patient satisfaction and staff members' perception on the WES-10 subscale of Self-realization. This exploratory study revealed that the working conditions of staff are related to both patient satisfaction and the patients' perceptions of the treatment environment. A satisfactory working environment for psychiatric staff members seems important for the quality of care perceived by patients. | 18,786,905 |
Identification of a link between the SAMP repeats of adenomatous polyposis coli tumor suppressor and the Src homology 3 domain of DDEF. | The adenomatous polyposis coli (APC) tumor suppressor protein is a multifunctional protein with a well characterized role in the Wnt signal transduction pathway and in cytoskeletal regulation. The SAMP repeats region of APC, an Axin-binding site, is known to be important for tumor suppression and for the developmental function of APC. We performed a yeast two-hybrid screening using the first SAMP motif-containing region of Xenopus APC as bait and obtained several SAMP binding candidates including DDEF2 (development and differentiation enhancing factor 2), which is an ADP-ribosylation factor (Arf) GTPase-activating protein (GAP (ArfGAP)) involved in the regulation of focal adhesions. In vitro and in cells the Src homology 3 (SH3) domain of DDEF2 and its close homolog, DDEF1, are associated with the SAMP motif of APC competitively with Axin1. Moreover, NMR chemical shift perturbation experiments revealed that the SAMP motif interacts at the same surface of the SH3 domain of DDEF as the known SH3 binding motif, PXXP. When fluorescent protein-tagged APC and DDEF are expressed in Xenopus A6 cells, co-localization at microtubule ends is observed. Overexpression and RNA interference experiments indicate that APC and DDEFs cooperatively regulate the distributions of microtubules and focal adhesions. Our findings reveal that the SAMP motif of APC specifically binds to the SH3 domains of DDEFs, providing new insights into the functions of APC in cell migration. | 18,786,926 |
Interaction between S100A8/A9 and annexin A6 is involved in the calcium-induced cell surface exposition of S100A8/A9. | The calcium binding S100A8/A9 complex (MRP8/14; calgranulin) is considered as an important proinflammatory mediator in acute and chronic inflammation and has recently gained attention as a molecular marker up-regulated in various human cancers. Here, we report that S100A8/A9 is expressed in breast cancer cell lines and is up-regulated by interleukin-1beta and tumor necrosis factor-alpha in SKBR3 and MCF-7 cells. We identified the phospholipid-binding protein annexin A6 as a potential S100A8/A9 binding protein by affinity chromatography. This finding was verified by Southwestern overlay experiments and by coimmunoprecipitation with the S100A8/A9-specific monoclonal antibody 27E10. Immunocytochemical experiments demonstrated that S100A8/A9 and annexin A6 colocalize in SKBR3 breast cancer cells predominantly in membranous structures. Upon calcium influx both S100A8/A9 and annexin A6 are exposed on the cell surface of SKBR3 cells. Subcellular fractionation studies suggested that after A23187 stimulation membrane association of S100A8/A9 is not enhanced. However, both S100A8/A9 and annexin A6 are exposed on the cell surface of SKBR3 cells upon calcium influx. Experiments with artificial liposomes indicated that S100A8/A9 is able to associate with membranes independently of both annexin A6 and independently of calcium. Finally, cell surface expression of S100A8/A9 could not be observed in A23187-treated A431 and HaCaT cells. Both cell lines are known to be devoid of annexin A6. Repression of annexin A6 expression by small interfering RNA in SKBR3 cells abolishes the cell surface exposition of S100A8/A9 upon calcium influx, suggesting that annexin A6 contributes to the calcium-dependent cell surface exposition of the membrane associated-S100A8/A9 complex. | 18,786,929 |
Factors affecting outcome of punctoplasty surgery: a review of 205 cases. | We reviewed retrospectively the indications, surgical techniques and outcomes of punctoplasty surgery for 205 consecutive patients in order to identify factors that influence success. We identified all patients who underwent punctoplasty surgery from April 2002 to June 2006 within the Royal Berkshire NHS Trust, UK. No patient had an additional procedure simultaneously. Hospital records were used to ascertain the proportion of patients who were appropriately assessed preoperatively, the anatomical and functional success rates for surgery and the patient satisfaction rate. We assessed the influence of surgical technique, grade of operating surgeon and the use of postoperative topical medication on these outcomes. Eighty-two per cent of patients had an appropriate preoperative assessment. Amongst these, the anatomical and functional success rates for punctoplasty surgery were 91% and 64%, respectively. The patient satisfaction rate was 71%. The grade of surgeon did not significantly affect outcome of punctoplasty (p = 0.4). The use of topical steroids postoperatively did not significantly improve surgical outcome (p = 0.7). There was no significant difference in anatomical success between a two-snip versus a three-snip punctoplasty technique (p = 0.7). However, in the presence of anatomical success the two-snip procedure gave significantly greater functional success (p = 0.03). This is the largest reported consecutive case series of isolated punctoplasty surgery. Overall anatomical success was high and the surgical technique, grade of surgeon and choice of postoperative medication did not significantly alter the outcome. Without adequate preoperative assessment a significant proportion of patients may undergo surgery inappropriately. Even with an adequate assessment anatomical success is not always followed by resolution of epiphora. | 18,786,958 |
IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. | We investigated the influence of cytokines on the expression of RANK ligand (RANKL) in fibroblast-like synoviocytes from RA patients (RA-FLS). RA-FLS were stimulated by IL-6, TNF-alpha, IL-17 and IL-1beta with or without soluble IL-6 receptor (sIL-6R) for 24 h. The expression of RANKL was measured by real-time PCR, western blotting and immunostaining. In proliferation assay, RA-FLS were cultured with cytokines for 3 days. RA-FLS were co-cultured with RAW cell in the presence of IL-6/sIL-6R for 3 days and then NFATc1 mRNA expression in RAW cells was examined. RA-FLS was cultured with parthenolide [PAR, signal transducer and activator of transcription (STAT) inhibitor] or PD98059 (PD, mitogen-activated protein kinase inhibitor) in the presence of IL-6/sIL-6R and then the influence of these drugs on phosphorylation of STAT3 and ERK1/2, and RANKL expression was examined. RANKL expression was induced by IL-6/sIL-6R (but not IL-6 alone) and by IL-1beta. On the other hand, TNF-alpha and IL-17 did not induce RANKL expression, although TNF-alpha, IL-17 or IL-1beta stimulated cell growth and IL-6 production. However, in the presence of sIL-6R, TNF-alpha or IL-17 induced RANKL expression. By the co-culture of RA-FLS, NFATc1 mRNA expression was induced in RAW cells. Finally, IL-6/sIL-6R induced phosphorylation of STAT3 and ERK1/2 in RA-FLS, and was completely inhibited by PAR and PD, respectively. PAR completely inhibited IL-6/sIL-6R-induced RANKL expression, but PD did not. IL-6/sIL-6R directly induced RANKL expression in RA-FLS and it is essential for RANKL induction by TNF-alpha and IL-17. Moreover, RANKL induction by IL-6/sIL-6R is mediated by the janus kinase/STAT signalling pathway. | 18,786,965 |
Adherence to Mediterranean diet and health status: meta-analysis. | To systematically review all the prospective cohort studies that have analysed the relation between adherence to a Mediterranean diet, mortality, and incidence of chronic diseases in a primary prevention setting. Meta-analysis of prospective cohort studies. English and non-English publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from 1966 to 30 June 2008. Studies reviewed Studies that analysed prospectively the association between adherence to a Mediterranean diet, mortality, and incidence of diseases; 12 studies, with a total of 1 574,299 subjects followed for a time ranging from three to 18 years were included. The cumulative analysis among eight cohorts (514,816 subjects and 33,576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94, 0.92 to 0.96), and incidence of Parkinson's disease and Alzheimer's disease (0.87, 0.80 to 0.96). Greater adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson's disease and Alzheimer's disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases. | 18,786,971 |
Adventitial transplantation of blood outgrowth endothelial cells in porcine haemodialysis grafts alleviates hypoxia and decreases neointimal proliferation through a matrix metalloproteinase-9-mediated pathway--a pilot study. | Purpose. We hypothesized that adventitial transplantation of blood outgrowth endothelial cells (BOEC) to the vein-to-graft anastomosis of polytetrafluoroethylene grafts will reduce neointimal hyperplasia by reducing hypoxia inducible factor-1alpha (HIF-1alpha), by increasing angiogenesis in a porcine model of chronic renal insufficiency with haemodialysis polytetrafluoroethylene grafts. Because matrix metalloproteinases (MMPs) have been shown to be involved with angiogenesis, the expression of MMPs and their inhibitors was determined. Chronic renal insufficiency was created by subtotal renal infarction and 28 days later, arteriovenous PTFE grafts were placed bilaterally from the carotid artery to the jugular vein. Autologous blood outgrowth endothelial cells labeled with Lac Z were transplanted to the adventitia of the vein-to-graft anastomosis using polyglycolic acid scaffolding and scaffolding only to other side (control). Animals were killed 14 days later and vessels were explanted from the vein-to-graft anastomosis of both sides and underwent immunohistochemical analysis, western blotting and zymography for HIF-1alpha, MMP-2, MMP-9, TIMP-1 and TIMP-2. BOEC were also made hypoxic and normoxic for 12, 24 and 48 h to determine protein expression for MMPs and TIMPs. Under hypoxia, BOEC significantly increased the expression of pro MMP-2 by 12 h and TIMP-2 by 24 h when compared to normoxic cells (P < 0.05). Transplantation of BOEC resulted in a significant decrease in both HIF-1alpha and intima-to-media ratio with a significant increase in both pro and active MMP-9 when compared to control vessels (P < 0.05). MMP-9 activity was localized to the neointima of the transplanted vessels by immunohistochemistry. There was increased CD31 density with engraftment of BOEC cells into the neointima of both the transplanted vessels compared to controls (P = NS). Transplantation of BOEC resulted in a significant decrease in intimal hyperplasia and HIF-1alpha with a significant increase in both pro and active MMP-9 that was localized to the neointima of transplanted vessels. The increase in MMP-9 offers a possible mechanism for angiogenesis and the reduced intima-to-media ratio. Furthermore, we observed that BOEC had homed to the neointima of the contralateral vessels that had increased levels of HIF-1alpha, suggesting that hypoxia may be an important stimulus for BOEC migration. | 18,786,975 |
Can medical students identify recreational drugs by name? | Recreational drug toxicity is a common reason for presentation to the Emergency Department. Knowledge of recreational drug names is important to allow targeted assessment of patients presenting with recreational drug toxicity. To assess final year medical student knowledge of proper and street names for recreational drugs. Questionnaire survey of final year medical students attending a revision lecture. There were two questionnaires used in this study. The first contained either proper names of recreational drugs or names sounding similar to recreational drugs or licensed pharmaceutical products; students were asked to identify which of these were recreational drugs. The second contained street names of recreational drugs and the students were asked to identify which recreational drug the street name referred to. One hundred and thirty-five students completed the questionnaire 1. The mean total score (+/-SD) of correct answers was 7.15 +/- 2.26 (range 2-13) out of a maximum of 15. One hundred and fifteen students completed questionnaire 2. The mean total score (+/-SD) of correctly identified street names was 11.0 +/- 2.6 (range 0-17) out of a maximum of 24. No individual student was able to correctly identify all the street names for the recreational drugs listed in the survey. We have shown that final year medical students have variable knowledge of both the proper and street names of recreational drugs. There is a need for improved education of medical students in the names of recreational drugs and the sources of information available to assist them in identifying what drugs an individual has taken. | 18,786,980 |
Group A human rotavirus genomics: evidence that gene constellations are influenced by viral protein interactions. | Group A human rotaviruses (HRVs) are the major cause of severe viral gastroenteritis in infants and young children. To gain insight into the level of genetic variation among HRVs, we determined the genome sequences for 10 strains belonging to different VP7 serotypes (G types). The HRVs chosen for this study, D, DS-1, P, ST3, IAL28, Se584, 69M, WI61, A64, and L26, were isolated from infected persons and adapted to cell culture to use as serotype references. Our sequencing results revealed that most of the individual proteins from each HRV belong to one of three genotypes (1, 2, or 3) based on their similarities to proteins of genogroup strains (Wa, DS-1, or AU-1, respectively). Strains D, P, ST3, IAL28, and WI61 encode genotype 1 (Wa-like) proteins, whereas strains DS-1 and 69M encode genotype 2 (DS-1-like) proteins. Of the 10 HRVs sequenced, 3 of them (Se584, A64, and L26) encode proteins belonging to more than one genotype, indicating that they are intergenogroup reassortants. We used amino acid sequence alignments to identify residues that distinguish proteins belonging to HRV genotype 1, 2, or 3. These genotype-specific changes cluster in definitive regions within each viral protein, many of which are sites of known protein-protein interactions. For the intermediate viral capsid protein (VP6), the changes map onto the atomic structure at the VP2-VP6, VP4-VP6, and VP7-VP6 interfaces. The results of this study provide evidence that group A HRV gene constellations exist and may be influenced by interactions among viral proteins during replication. | 18,786,998 |
Engineered expression of the TLR5 ligand flagellin enhances paramyxovirus activation of human dendritic cell function. | The paramyxovirus simian virus 5 (SV5) is a poor activator of human dendritic cell (DC) maturation pathways in vitro, and infected DC do not upregulate cell surface costimulatory proteins or secretion of immunomodulatory cytokines. We evaluated the hypothesis that activation of SV5-infected DC would be enhanced by engineering SV5 to express a Toll-like-receptor (TLR) ligand. To test this hypothesis, a novel virus was engineered such that the gene encoding an intracellular form of the TLR5 ligand flagellin was expressed from the genome of wild-type (WT) SV5 (SV5-flagellin). Cells infected in vitro with the flagellin-expressing virus released low levels of biologically active flagellin, which was capable of stimulating TLR5 signaling. Infection of human peripheral blood mononuclear cell-derived immature DC with SV5-flagellin resulted in enhanced levels of interleukin-6 (IL-6) and IL-12 compared to infection with DC with the parental virus, WT SV5. In contrast to cytokine induction, the flagellin-expressing virus did not appreciably increase DC surface expression of the costimulatory molecule CD80 or CD86 above the level seen with WT SV5 alone. In mixed-culture assays, DC infected with the flagellin-expressing virus were more effective at activating gamma interferon secretion from both CD8(+) and CD4(+) allogeneic T cells than DC infected with WT SV5. Our results with SV5-directed intracellular expression of flagellin may be applicable to other vectors or pathogenic viruses where overcoming impairment of DC activation could contribute to the development of safer and more effective vaccines. | 18,787,007 |
Impact of epitope specificity and precursor maturation in pro-B-type natriuretic peptide measurement. | Cardiac-derived natriuretic peptides are sensitive plasma markers of cardiac dysfunction. Recent reports have disclosed a more complex molecular heterogeneity of B-type natriuretic peptide precursor (proBNP)-derived peptides than previously suggested. In this study, we examined the impact of epitope specificity and precursor maturation on plasma measurement of proBNP-derived peptides. We compared 2 assays, N-terminal proBNP and proBNP 1-76, in a randomly collected set of human plasma specimens (n = 370). Additionally, we evaluated the clinical performance of 4 assays with different epitope specificities in a cohort of elderly patients presenting with symptoms associated with heart failure (n = 415). Comparison of N-terminal proBNP with proBNP 1-76 measurement in plasma revealed a high correlation on regression analysis (r(2) = 0.91, P < 0.0001). Nevertheless, the proBNP 1-76 assay measured lower concentrations in the high range than the N-terminal proBNP assay. Correlations between assay measurements in a clinical setting were comparable for all the assays (r(2) approximately 0.57-0.83), and ROC analyses revealed area-under-the-curve values ranging between 0.77 and 0.81 for identifying reduced left ventricular ejection fraction. In parallel, all assays displayed comparable abilities in predicting long-term mortality. Our results reveal marked assay differences in analytical assay comparison, contrasting the overall comparable clinical performance in cardiovascular diagnostics or prognosis in the elderly. | 18,787,017 |
The role of redox signaling in cardiac hypertrophy induced by experimental hyperthyroidism. | This study was conducted to test whether oxidative stress activates the intracellular protein kinase B (AKT1) signaling pathway, which culminates with cardiac hypertrophy in experimental hyperthyroidism. Male Wistar rats were divided into four groups: control, vitamin E, thyroxine (T(4)), and T(4)+vitamin E. Hyperthyroidism was induced by T(4) administration (12 mg/l in drinking water for 28 days). Vitamin E treatment was given during the same period via s.c. injections (20 mg/kg per day). Morphometric and hemodynamic parameters were evaluated at the end of the 4-week treatment period. Protein oxidation, redox state (reduced glutathione, GSH/glutathione dissulfide, GSSG), vitamin C, total radical-trapping antioxidant potential (TRAP), hydrogen peroxide (H2O2), and nitric oxide metabolites (NO(X)) were measured in heart homogenates. The p-AKT1/AKT1 ratio, p-glycogen-synthase kinase (GSK)3B/GSK3B ratio, FOS, and JUN myocardial protein expression were also quantified by western blot after 4 weeks. Increases in biochemical parameters, such as protein oxidation (41%), H2O2 (62%), and NO(X) (218%), and increase in the left ventricular end-diastolic pressure were observed in the T(4) group. T(4) treatment also caused a decrease in GSH/GSSG ratio (83%), vitamin C (34%), and TRAP (55%). These alterations were attenuated by vitamin E administration to the hyperthyroid rats. Expression of p-AKT1/AKT1, p-GSK3B/GSK3B, FOS, and JUN were elevated in the T(4) group (by 69, 37, 130, and 33% respectively), whereas vitamin E administration promoted a significant reduction in their expression. These results indicate that oxidative stress plays an important role in cardiac hypertrophy, and suggest redox activation of AKT1 and JUN/FOS signaling pathways with H2O2 acting as a possible intracellular mediator in this adaptive response to experimental hyperthyroidism. | 18,787,053 |
Canalicular Mrp2 localization is reversibly regulated by the intracellular redox status. | Oxidative stress is known to be a common feature of cholestatic syndrome. We have described the internalization of multidrug resistance-associated protein 2 (Mrp2), a biliary transporter involved in bile salt-independent bile flow, under acute oxidative stress, and a series of signaling pathways finally leading to the activation of novel protein kinase C were involved in this mechanism; however, it has been unclear whether the internalized Mrp2 localization was relocalized to the canalicular membrane when the intracellular redox status was recovered from oxidative stress. In this study, we demonstrated that decreased canalicular expression of Mrp2 induced by tertiary-butyl hydroperoxide (t-BHP) was recovered to the canalicular membrane by the replenishment of GSH by GSH-ethyl ester, a cell-permeable form of GSH. Moreover, pretreatment of isolated rat hepatocytes with colchicine and PKA inhibitor did not affect the t-BHP-induced Mrp2 internalization process but did prevent the Mrp2 recycling process induced by GSH replenishment. Moreover, intracellular cAMP concentration similarly changed with the change of intracellular GSH content. Taken together, our data clearly indicate that the redox-sensitive balance of PKA/PKC activation regulates the reversible Mrp2 localization in two different pathways, the microtubule-independent internalization pathway and -dependent recycling pathway of Mrp2. | 18,787,061 |
Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. | Live probiotic bacteria are effective in reducing gut permeability and inflammation. We have previously shown that probiotics release peptide bioactive factors that modulate epithelial resistance in vitro. The objectives of this study were to determine the impact of factors released from Bifidobacteria infantis on intestinal epithelial cell permeability and tight junction proteins and to assess whether these factors retain their bioactivity when administered to IL-10-deficient mice. B. infantis conditioned medium (BiCM) was applied to T84 human epithelial cells in the presence and absence of TNF-alpha and IFN-gamma. Transepithelial resistance (TER), tight junction proteins [claudins 1, 2, 3, and 4, zonula occludens (ZO)-1, and occludin] and MAP kinase activity (p38 and ERK) were examined. Acute effects of BiCM on intestinal permeability were assessed in colons from IL-10-deficient mice in Ussing chambers. A separate group of IL-1-deficient mice was treated with BiCM for 4 wk and then assessed for intestinal histological injury, cytokine levels, epithelial permeability, and immune response to bacterial antigens. In T84 cells, BiCM increased TER, decreased claudin-2, and increased ZO-1 and occludin expression. This was associated with enhanced levels of phospho-ERK and decreased levels of phospho-p38. BiCM prevented TNF-alpha- and IFN-gamma-induced drops in TER and rearrangement of tight junction proteins. Inhibition of ERK prevented the BiCM-induced increase in TER and attenuated the protection from TNF-alpha and IFN-gamma. Oral BiCM administration acutely reduced colonic permeability in mice whereas long-term BiCM treatment in IL-10-deficient mice attenuated inflammation, normalized colonic permeability, and decreased colonic and splenic IFN-gamma secretion. In conclusion, peptide bioactive factors from B. infantis retain their biological activity in vivo and are effective in normalizing gut permeability and improving disease in an animal model of colitis. The effects of BiCM are mediated in part by changes in MAP kinases and tight junction proteins. | 18,787,064 |
Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells. | Previously, we have demonstrated that forkhead box O3a (FOXO3a) overexpression increased p27(Kip1) promoter activity and protein expression, whereas it decreased proliferation in muscle precursor cells (MPCs). The objectives of the present study were to 1) locate and identify FOXO regulatory elements in the rat p27(Kip1) promoter using deletion analysis of a promoter/reporter construct and 2) determine if age-related differences exist in FOXO-induced p27(Kip1) expression. The full-length (-4.0/+0.4 kb) rat p27(Kip1) promoter construct revealed that both FOXO1 and FOXO3a induced an increase in transcriptional activity. Interestingly, MPCs isolated from old animals exhibited an increased FOXO3a-induced p27(Kip1) promoter activity compared with MPCs isolated from young animals. Deletion of a 253-bp portion of the 5'-untranslated region (UTR) resulted in a significant decrease in FOXO-induced p27(Kip1) promoter expression. Site-specific mutation of a daf-16 family protein-binding element (DBE) within this 253-bp portion of the 5'-UTR also demonstrated a decrease in FOXO-induced p27(Kip1) promoter expression. These data suggest that a putative FOXO regulatory element located in the 5'-UTR of the rat p27(Kip1) gene plays a role in the age-dependent differences in FOXO3a-dependent p27(Kip1) promoter expression. These findings have implications for developing treatment strategies aimed at increasing the proliferation of MPCs and regenerative capacity of aged skeletal muscle. | 18,787,071 |
Oxidant-induced inhibition of the plasma membrane Ca2+-ATPase in pancreatic acinar cells: role of the mitochondria. | Impairment of the normal spatiotemporal pattern of intracellular Ca(2+) ([Ca(2+)](i)) signaling, and in particular, the transition to an irreversible "Ca(2+) overload" response, has been implicated in various pathophysiological states. In some diseases, including pancreatitis, oxidative stress has been suggested to mediate this Ca(2+) overload and the associated cell injury. We have previously demonstrated that oxidative stress with hydrogen peroxide (H(2)O(2)) evokes a Ca(2+) overload response and inhibition of plasma membrane Ca(2+)-ATPase (PMCA) in rat pancreatic acinar cells (Bruce JI and Elliott AC. Am J Physiol Cell Physiol 293: C938-C950, 2007). The aim of the present study was to further examine this oxidant-impaired inhibition of the PMCA, focusing on the role of the mitochondria. Using a [Ca(2+)](i) clearance assay in which mitochondrial Ca(2+) uptake was blocked with Ru-360, H(2)O(2) (50 microM-1 mM) markedly inhibited the PMCA activity. This H(2)O(2)-induced inhibition of the PMCA correlated with mitochondrial depolarization (assessed using tetramethylrhodamine methylester fluorescence) but could occur without significant ATP depletion (assessed using Magnesium Green fluorescence). The H(2)O(2)-induced PMCA inhibition was sensitive to the mitochondrial permeability transition pore (mPTP) inhibitors, cyclosporin-A and bongkrekic acid. These data suggest that oxidant-induced opening of the mPTP and mitochondrial depolarization may lead to an inhibition of the PMCA that is independent of mitochondrial Ca(2+) handling and ATP depletion, and we speculate that this may involve the release of a mitochondrial factor. Such a phenomenon may be responsible for the Ca(2+) overload response, and for the transition between apoptotic and necrotic cell death thought to be important in many disease states. | 18,787,078 |
Eccentric contractions do not induce rhabdomyolysis in malignant hyperthermia susceptible mice. | Recent studies suggest a link between exercise-induced rhabdomyolysis and mutations of the ryanodine receptor (RYR1) associated with malignant hyperthermia (MH). We hypothesized that MH-susceptible mice (RYR1Y522S/wt) would exhibit greater anterior crural muscle [tibialis anterior (TA) and extensor digitorum longus (EDL) muscles] damage and strength deficits following the performance of a single or repeated bouts of eccentric contractions compared with wild-type (WT) mice. After a single injury bout, RYR1Y522S/wt mice produced more isometric torque than WT mice immediately and 3 and 7 days postinjury. Moreover, EDL muscle isometric specific force deficits were fully recovered for RYR1Y522S/wt but not WT mice 14 days postinjury. The percentage of fibers in TA muscle exhibiting signs of muscle damage 7 and 14 days postinjury were at least three times less in RYR1Y522S/wt than in WT mice. Uninjured and injured EDL muscle from RYR1Y522S/wt mice also displayed greater S-glutathionylation of RYR1 than that from WT mice. During the weekly injury bouts, torque production by RYR1Y522S/wt mice was fully recovered before the third and fourth injury bouts, whereas torque was still reduced for WT mice. Three days after multiple injury bouts, there were approximately 50% fewer fibers exhibiting signs of muscle damage in RYR1Y522S/wt than in WT TA muscle. These findings indicate that the RYR1Y522S/wt mutation protects skeletal muscle from exercise-induced muscle injury and do not support a direct association between MH susceptibility and contraction-induced rhabdomyolysis when core temperature is maintained at lower physiological temperatures during exercise. | 18,787,086 |
Heme oxygenase-1 prevents airway mucus hypersecretion induced by cigarette smoke in rodents and humans. | We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n = 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT)(n) in the HO-1 promoter gene (>33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6%, P = 0.047). No such results were observed in those who had never smoked (n = 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS. | 18,787,101 |
Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation. | Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy. | 18,787,105 |
The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake. | Although cell-penetrating peptides are able to deliver cargo into cells, their uptake mechanism is still not fully understood and needs to be elucidated to improve their delivery efficiency. Herein, we present evidence of a new mechanism involved in uptake, the membrane repair response. Recent studies have suggested that there might be a direct penetration of peptides in parallel with different forms of endocytosis. The direct penetration of hydrophilic peptides through the hydrophobic plasma membrane, however, is highly controversial. Three proteins involved in target cell apoptosis--perforin, granulysin, and granzymes--share many features common in uptake of cell-penetrating peptides (e.g., they bind proteoglycans). During perforin uptake, the protein activates the membrane repair response, a resealing mechanism triggered in cells with injured plasma membrane, because of extracellular calcium influx. On activation of the membrane repair response, internal vesicles are mobilized to the site of the disrupted plasma membrane, resealing it within seconds. In this study, we have used flow cytometry, fluorescence, and electron microscopy, together with high-performance liquid chromatography and mass spectrometry, to present evidence that the membrane repair response is able to mask damages caused during cell-penetrating peptide uptake, thus preventing leakage of endogenous molecules out of the cell. | 18,787,109 |
Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation. | A recently determined set of 20 NMR-derived conformations of a 48-residue all-alpha-helical protein, (PDB ID code 2JVD), is validated here by comparing the observed (13)C(alpha) chemical shifts with those computed at the density functional level of theory. In addition, a recently introduced physics-based method, aimed at determining protein structures by using NOE-derived distance constraints together with observed and computed (13)C(alpha) chemical shifts, was applied to determine a new set of 10 conformations, (Set-bt), as a blind test for the same protein. A cross-validation of these two sets of conformations in terms of the agreement between computed and observed (13)C(alpha) chemical shifts, several stereochemical quality factors, and some NMR quality assessment scores reveals the good quality of both sets of structures. We also carried out an analysis of the agreement between the observed and computed (13)C(alpha) chemical shifts for a slightly longer construct of the protein solved by x-ray crystallography at 2.0-A resolution (PDB ID code 3BHP) with an identical amino acid residue sequence to the 2JVD structure for the first 46 residues. Our results reveal that both of the NMR-derived sets, namely 2JVD and Set-bt, are somewhat better representations of the observed (13)C(alpha) chemical shifts in solution than the 3BHP crystal structure. In addition, the (13)C(alpha)-based validation analysis appears to be more sensitive to subtle structural differences across the three sets of structures than any other NMR quality-assessment scores used here, and, although it is computationally intensive, this analysis has potential value as a standard procedure to determine, refine, and validate protein structures. | 18,787,110 |
Quantitative visualization of passive transport across bilayer lipid membranes. | The ability to predict and interpret membrane permeation coefficients is of critical importance, particularly because passive transport is crucial for the effective delivery of many pharmaceutical agents to intracellular targets. We present a method for the quantitative measurement of the permeation coefficients of protonophores by using laser confocal scanning microscopy coupled to microelectrochemistry, which is amenable to precise modeling with the finite element method. The technique delivers well defined and high mass transport rates and allows rapid visualization of the entire pH distribution on both the cis and trans side of model bilayer lipid membranes (BLMs). A homologous series of carboxylic acids was investigated as probe molecules for BLMs composed of soybean phosphatidylcholine. Significantly, the permeation coefficient decreased with acyl tail length contrary to previous work and to Overton's rule. The reasons for this difference are considered, and we suggest that the applicability of Overton's rule requires re-evaluation. | 18,787,114 |
CD4 memory T cells divide poorly in response to antigen because of their cytokine profile. | Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFNgamma. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFNgamma increased the proliferation of the memory cells. | 18,787,120 |
Modes of heme binding and substrate access for cytochrome P450 CYP74A revealed by crystal structures of allene oxide synthase. | Cytochrome P450s exist ubiquitously in all organisms and are involved in many biological processes. Allene oxide synthase (AOS) is a P450 enzyme that plays a key role in the biosynthesis of oxylipin jasmonates, which are involved in signal and defense reactions in higher plants. The crystal structures of guayule (Parthenium argentatum) AOS (CYP74A2) and its complex with the substrate analog 13(S)-hydroxyoctadeca-9Z,11E-dienoic acid have been determined. The structures exhibit a classic P450 fold but possess a heme-binding mode with an unusually long heme binding loop and a unique I-helix. The structures also reveal two channels through which substrate and product may access and leave the active site. The entrances are defined by a loop between beta3-2 and beta3-3. Asn-276 in the substrate binding site may interact with the substrate's hydroperoxy group and play an important role in catalysis, and Lys-282 at the entrance may control substrate access and binding. These studies provide both structural insights into AOS and related P450s and a structural basis to understand the distinct reaction mechanism. | 18,787,124 |
Atypical E2F activity restrains APC/CCCS52A2 function obligatory for endocycle onset. | The endocycle represents an alternative cell cycle that is activated in various developmental processes, including placental formation, Drosophila oogenesis, and leaf development. In endocycling cells, mitotic cell cycle exit is followed by successive doublings of the DNA content, resulting in polyploidy. The timing of endocycle onset is crucial for correct development, because polyploidization is linked with cessation of cell division and initiation of terminal differentiation. The anaphase-promoting complex/cyclosome (APC/C) activator genes CDH1, FZR, and CCS52 are known to promote endocycle onset in human, Drosophila, and Medicago species cells, respectively; however, the genetic pathways governing development-dependent APC/C(CDH1/FZR/CCS52) activity remain unknown. We report that the atypical E2F transcription factor E2Fe/DEL1 controls the expression of the CDH1/FZR orthologous CCS52A2 gene from Arabidopsis thaliana. E2Fe/DEL1 misregulation resulted in untimely CCS52A2 transcription, affecting the timing of endocycle onset. Correspondingly, ectopic CCS52A2 expression drove cells into the endocycle prematurely. Dynamic simulation illustrated that E2Fe/DEL1 accounted for the onset of the endocycle by regulating the temporal expression of CCS52A2 during the cell cycle in a development-dependent manner. Analogously, the atypical mammalian E2F7 protein was associated with the promoter of the APC/C-activating CDH1 gene, indicating that the transcriptional control of APC/C activator genes by atypical E2Fs might be evolutionarily conserved. | 18,787,127 |
Distinct TRP channels are required for warm and cool avoidance in Drosophila melanogaster. | The ability to sense and respond to subtle variations in environmental temperature is critical for animal survival. Animals avoid temperatures that are too cold or too warm and seek out temperatures favorable for their survival. At the molecular level, members of the transient receptor potential (TRP) family of cation channels contribute to thermosensory behaviors in animals from flies to humans. In Drosophila melanogaster larvae, avoidance of excessively warm temperatures is known to require the TRP protein dTRPA1. Whether larval avoidance of excessively cool temperatures also requires TRP channel function, and whether warm and cool avoidance use the same or distinct TRP channels has been unknown. Here we identify two TRP channels required for cool avoidance, TRPL and TRP. Although TRPL and TRP have previously characterized roles in phototransduction, their function in cool avoidance appears to be distinct, as neither photoreceptor neurons nor the phototransduction regulators NORPA and INAF are required for cool avoidance. TRPL and TRP are required for cool avoidance; however they are dispensable for warm avoidance. Furthermore, cold-activated neurons in the larvae are required for cool but not warm avoidance. Conversely, dTRPA1 is essential for warm avoidance, but not cool avoidance. Taken together, these data demonstrate that warm and cool avoidance in the Drosophila larva involves distinct TRP channels and circuits. | 18,787,131 |
Comment on "A global map of human impact on marine ecosystems". | Halpern et al. (Reports, 15 February 2008, p. 948) integrated spatial data on 17 drivers of change in the oceans to map the global distribution of human impact. Although fishery catches are a dominant driver, the data reflect activity while impacts occur at different space and time scales. Failure to account for this spatial disconnection could lead to potentially misleading conclusions. | 18,787,153 |
Cooling, heating, generating power, and recovering waste heat with thermoelectric systems. | Thermoelectric materials are solid-state energy converters whose combination of thermal, electrical, and semiconducting properties allows them to be used to convert waste heat into electricity or electrical power directly into cooling and heating. These materials can be competitive with fluid-based systems, such as two-phase air-conditioning compressors or heat pumps, or used in smaller-scale applications such as in automobile seats, night-vision systems, and electrical-enclosure cooling. More widespread use of thermoelectrics requires not only improving the intrinsic energy-conversion efficiency of the materials but also implementing recent advancements in system architecture. These principles are illustrated with several proven and potential applications of thermoelectrics. | 18,787,160 |
Imaging of transient structures using nanosecond in situ TEM. | The microstructure and properties of a material depend on dynamic processes such as defect motion, nucleation and growth, and phase transitions. Transmission electron microscopy (TEM) can spatially resolve these nanoscale phenomena but lacks the time resolution for direct observation. We used a photoemitted electron pulse to probe dynamic events with "snapshot" diffraction and imaging at 15-nanosecond resolution inside of a dynamic TEM. With the use of this capability, the moving reaction front of reactive nanolaminates is observed in situ. Time-resolved images and diffraction show a transient cellular morphology in a dynamically mixing, self-propagating reaction front, revealing brief phase separation during cooling, and thus provide insights into the mechanisms driving the self-propagating high-temperature synthesis. | 18,787,163 |
Postseismic relaxation along the San Andreas fault at Parkfield from continuous seismological observations. | Seismic velocity changes and nonvolcanic tremor activity in the Parkfield area in California reveal that large earthquakes induce long-term perturbations of crustal properties in the San Andreas fault zone. The 2003 San Simeon and 2004 Parkfield earthquakes both reduced seismic velocities that were measured from correlations of the ambient seismic noise and induced an increased nonvolcanic tremor activity along the San Andreas fault. After the Parkfield earthquake, velocity reduction and nonvolcanic tremor activity remained elevated for more than 3 years and decayed over time, similarly to afterslip derived from GPS (Global Positioning System) measurements. These observations suggest that the seismic velocity changes are related to co-seismic damage in the shallow layers and to deep co-seismic stress change and postseismic stress relaxation within the San Andreas fault zone. | 18,787,165 |
Expansion of T-cell receptor zeta dim effector T cells in acute coronary syndromes. | The T-cell receptor zeta (TCR zeta)-chain is a master sensor and regulator of lymphocyte responses. Loss of TCR zeta-chain expression has been documented during infectious and inflammatory diseases and defines a population of effector T cells (TCR zeta(dim) T cells) that migrate to inflamed tissues. We assessed the expression and functional correlates of circulating TCR zeta(dim) T cells in coronary artery disease. We examined the expression of TCR zeta-chain by flow cytometry in 140 subjects. Increased peripheral blood CD4(+) TCR zeta(dim) T cells were found in patients with acute coronary syndromes (ACS, n=66; median 5.3%, interquartile 2.6 to 9.1% of total CD4(+) T cells; P<0.0001) compared to chronic stable angina (CSA, n=32; 1.6%; 1.0 to 4.1%) and controls (n=42; 1.5%; 0.5 to 2.9%). Such increase was significantly greater in ACS patients with elevated levels of C-reactive protein, and it persisted after the acute event. Moreover, TCR zeta(dim) cells were also more represented within CD8(+) T cell, NK, and CD4(+)CD28(null) T cell subsets in ACS compared to CSA and controls. Finally, CD4(+) and CD8(+) TCR zeta(dim) T cells isolated from ACS displayed an enhanced transendothelial migratory capacity. TCR zeta(dim) T cells, an effector T-cell subset with transendothelial migratory ability, are increased in ACS, and may be implicated in coronary instability. | 18,787,188 |
Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. | Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux. | 18,787,193 |
Novel fold of VirA, a type III secretion system effector protein from Shigella flexneri. | VirA, a secreted effector protein from Shigella sp., has been shown to be necessary for its virulence. It was also reported that VirA might be related to papain-like cysteine proteases and cleave alpha-tubulin, thus facilitating intracellular spreading. We have now determined the crystal structure of VirA at 3.0 A resolution. The shape of the molecule resembles the letter "V," with the residues in the N-terminal third of the 45-kDa molecule (some of which are disordered) forming one clearly identifiable domain, and the remainder of the molecule completing the V-like structure. The fold of VirA is unique and does not resemble that of any known protein, including papain, although its N-terminal domain is topologically similar to cysteine protease inhibitors such as stefin B. Analysis of the sequence conservation between VirA and its Escherichia coli homologs EspG and EspG2 did not result in identification of any putative protease-like active site, leaving open a possibility that the biological function of VirA in Shigella virulence may not involve direct proteolytic activity. | 18,787,201 |
Transformation by retroviral vectors of bone marrow-derived mesenchymal cells induces mitochondria-dependent cAMP-sensitive reactive oxygen species production. | Retroviral vectors are used in human gene therapy trials to stably introduce therapeutic genes in the genome of patients' cells. Their applicability, however, is frustrated by the limited viability of transformed cells and/or by risks linked to selection of oncogene-mutated clones. The reasons for these drawbacks are not yet completely understood. In this study, we show that LXSN-NeoR gene/interleukin-7-engineered mesenchymal stromal cells exhibited a marked enhancement of reactive oxygen species production compared with untransfected cells. This effect resulted to be independent on the product of the gene carried by the retroviral vehicle as it was reproducible in cells transfected with the empty vector alone. Stable transfection of mesenchymal stromal cells with the different retroviral vectors pBabe-puro and PINCO-puro and the lentiviral vector pSico PGK-puro caused similar redox imbalance, unveiling a phenomenon of more general impact. The enhanced production of reactive oxygen species over the basal level was attributable to mitochondrial dysfunction and brought back to altered activity of the NADH-CoQ oxidoreductase (complex I) of the respiratory chain. The oxidative stress in transfected mesenchymal stem cells was completely reversed by treatment with a cAMP analog, thus pointing to alteration in the protein kinase A-dependent signaling pathway of the host cell. Transfection of mesenchymal stromal cells with a PINCO-parental vector harboring the green fluorescent protein gene as selection marker in place of the puromycin-resistance gene resulted in no alteration of the redox phenotype. These novel findings provide insights and caveats to the applicability of cell- or gene-based therapies and indicate possible intervention to improve them. Disclosure of potential conflicts of interest is found at the end of this article. | 18,787,213 |
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