title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Comparison of kidney size between patients with Balkan endemic nephropathy and other kidney diseases. | The aim of this study was to assess the relationship between kidney dimensions and creatinine clearance (Ccr) in patients with Balkan endemic nephropathy (BEN), nephrosclerosis (NSc), glomerulonephritis (GN), diabetic nephropathy (DN) and in healthy persons. The main objective was to find out at which stage of BEN the kidneys start to shrink. The study involved 84 patients with BEN, 39 with NSc, 56 with GN, 55 with DN, and 52 healthy subjects, allocated to group 1 (n = 28) sex- and age-matched with BEN/NSc patients, or group 2 (n = 24) sex- and age-matched with GN/DN patients. Based on Ccr, patients were classified according to the NKF/DOQI guidelines. The kidney dimensions of BEN patients in all stages of the disease were significantly shorter than those of healthy controls and patients with GN and DN. In stages 3-5, BEN patients had significantly smaller kidneys than patients with NSc. Patients with NSc had smaller kidney dimensions than controls and GN/DN patients but all of these differences were not significant. BEN patients had significantly smaller kidneys than sex- and age-matched healthy persons and patients with GN and DN in all stages of the disease and patients with NSc in stages 3-5 of the disease. | 18,781,078 |
p27Kip1 promotes migration of metastatic hepatocellular carcinoma cells. | p27(Kip1) (p27) is a member of the Cip/Kip family of cyclin/cyclin-dependent kinase inhibitors (CKIs), and its CKI-independent function regarding cell motility modulation has been discovered. However, it is controversial whether p27 promotes or inhibits cell migration. This study investigates the migration regulatory role of p27 in metastatic hepatocellular carcinoma (HCC) cells. RNA interference, RhoA-GTP pull-down assay, Western blots, immunostaining, transwell and wound-healing assays were used. High levels of p27 and phosphorylated p27 (Ser10) were detected in metastatic HCC cells, MHCC97L and MHCC97H, when compared with nonmetastatic HCC cells, PLC and Hep3B. We hypothesized that p27 is responsible for metastasis-related migration in HCC cells and tested the hypothesis by using the p27 RNA interference approach. Increased RhoA activity was observed when p27 was knocked down in MHCC97L cells, which further led to stress fiber formation and decreased cell migration and wound healing. Moreover, high p27 and low stathmin expression of metastatic HCC cells indicated that migration inhibition by p27-stathmin interaction might not be the major regulatory pathway in metastatic HCC cells. p27 promotes cell migration in metastatic HCC cells through the regulation of RhoA activity. | 18,781,093 |
[The evaluation of the distal airway inflammation of well controlled asthmatic patients using sputum induction by inhalation of 10% hypertonic saline for 15 minutes]. | As the clinical importance of treatment to asthmatic distal airway has been recognized, this study aimed to evaluate the efficacy of the 10% hypertonic saline-induced 15 minutes long-inhaled method to assess the inflammatory situation in the distal airways. The subjects were 16 healthy volunteers and 29 patients with well controlled asthma. They inhaled 5% or 10% hypertonic saline for 15 minutes and the sputum induction rates and induced times were measured. We also investigated the values of surfactant protein D (SP-D) and eosinophil cationic protein (ECP) both in early- and late-phase induced sputum, together with pulmonary function indexes, and the patients' impressions of the method. The sputum induction rates with 10% hypertonic saline inhalation in both healthy volunteer group and well controlled asthmatic patients group were significantly high compared with those with 5% hypertonic saline inhalation; 75.0% (p=0.004) and 75.9% (p=0.007), respectively. The SP-D levels in late-phase sputum in both healthy volunteer group and well controlled asthmatic patients group significantly elevated compared with those in the early-phase: p=0.045 and p=0.007, respectively. The SP-D levels in late-phase sputum significantly correlated to those of ECP in the well controlled asthmatic patients group (r=0.527, p=0.017). The pulmonary function index FEV1.0% of 18 well controlled asthmatic patients (62.1%) attenuated 2.9+/-2.5% soon after finishing the 10% hypertonic saline inhalation, and recovered after an additional 15 minutes rest. 70 approximately 80% of the subjects in both groups answered that they felt no strain in using the inhaled method. The late-phase sputum obtained by the 10% hypertonic saline-induced 15 minutes long-inhaled method may be useful in evaluating the inflammatory situation in the distal airways. | 18,781,105 |
Pediatric anxiety disorders: management in primary care. | Anxiety disorders are common in children and adolescents, with prevalence rates varying from 6 to 20%. These disorders can result in significant academic, social, and familial impairment. Early identification in pediatric primary care and effective management may help improve outcomes. Self-report measures of pediatric anxiety can supplement the clinical interview and assist in screening children and adolescents for separation anxiety disorder, generalized anxiety disorder, and social phobia. Substantial evidence supports the use of cognitive behavioral therapy and selective serotonin reuptake inhibitors in the treatment of pediatric anxiety disorders. Although treatment with serotonin reuptake inhibitors may lead to a small increase in the risk for suicidal ideation in children and adolescents, the risk benefit ratio for serotonin reuptake inhibitor use in pediatric anxiety disorders is favorable with appropriate monitoring. Although evidence-support treatments have emerged for pediatric anxiety disorders, their effectiveness in pediatric primary care has not been evaluated. Future research should assess the delivery of manual-based cognitive behavioral therapy for anxiety disorders by mental health professionals integrated into the primary care settings, the effectiveness of serotonin reuptake inhibitor prescription by pediatric primary care clinicians, and the use of collaborative models for providing anxiety treatments for children and adolescents in primary care settings. | 18,781,116 |
Fusion in the ETS gene family and prostate cancer. | It has recently been shown that the majority of prostate cancers harbour a chromosomal rearrangement that fuses the gene for an androgen-regulated prostate-specific serine protease, TMPRSS2, with a member of the ETS family of transcription factors, most commonly ERG. These are among the most common genetic alterations in any human solid tumour. This knowledge may provide us with clues to prostate carcinogenesis, and may lead to the development of important molecular-based biomarkers for patients with localised prostate cancer. The most common variant is fusion between the 5'-untranslated region of TMPRSS2 and the 3' region of ERG. However, over 20 other fusion variants have now been described (involving over 10 different genes) and the number of variants continues to grow. Fusion products can be identified by several techniques, including FISH, RT-PCR, and expression profiling using exon arrays. The protein products associated with the fusion transcripts have not been characterised, and the phenotypic expression of the various products of gene fusion on prostate cancer histology, or on the clinical course of cancer, are not yet understood. Several early cohort studies suggest that the presence of the TMPRSS2:ERG fusion product is associated with relatively poor cancer-specific survival. Studies that examine how individual variants and their associated phenotypes affect prostate cancer presentation and progression are required. | 18,781,147 |
Trends in large-scale mouse mutagenesis: from genetics to functional genomics. | The primary goal of mouse mutagenesis programmes is to develop a fundamental research infrastructure for mammalian functional genomics and to produce human disease models. Many large-scale programmes have been ongoing since 1997; these culminated in the International Knockout Mouse Consortium (IKMC) in 2007 with the aim to establish knockout and conditional mouse strains for all mouse genes. This article traces the origins and rationale of these large-scale mouse mutagenesis programmes. | 18,781,157 |
Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex- and population-specific genetic effects. | Stature (adult body height) and body mass index (BMI) have a strong genetic component explaining observed variation in human populations; however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population- and sex-specific analyses as well. For stature, we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23, as well as 15q26 and 19q13, which have not been linked to stature previously. For BMI, we found evidence for two loci: one on 7q35 and another on 11q22, both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of (1) combining data to maximize the sample size and (2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping. | 18,781,184 |
The E-cadherin (CDH1)--160 C/A polymorphism and prostate cancer risk: a meta-analysis. | Published data on the association between E-cadherin (CDH1) -160 C/A polymorphism and prostate cancer (PCA) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A logistic regression approach proposed for molecular association studies was used to estimate a biological model of the gene effect. A total of 11 studies including 2637 cases and 2673 controls were involved in this meta-analysis. Logistic regression analysis indicated that the CDH1 -160 C/A genotypes were associated with PCA risk. The genetic model test indicated that the genetic model was most likely to be dominant (CA+AA vs CC). Overall, meta-analysis indicated that the -160A allele carriers (CA+AA) had a 21% elevated risk of PCA, when compared with the homozygotes (CC) (odds ratio (OR)=1.21; 95% confidence interval (CI): 0.97-1.51; P=0.090, P(heterogeneity)=0.001). In the subgroup analyses by ethnicity, significantly elevated risks were associated with -160 variant genotypes (CA+AA) in both European and Asian populations (OR=1.24; 95% CI: 1.08-1.43; P=0.003, P(heterogeneity)=0.220 and OR=1.54; 95% CI: 1.23-1.93; P<0.001, P(heterogeneity)=0.200). However, no significant associations were found in Africans (OR=0.59; 95% CI: 0.32-1.09; P=0.090, P(heterogeneity)=0.070). Although some modest bias could not be eliminated, this meta-analysis suggests that the CDH1 -160A allele is a low-penetrant risk factor for developing PCA, especially in Europeans and Asians. | 18,781,193 |
Uric acid nephrolithias in the era of noncontrast computed tomography. | We report 2 patients who presented with uric acid renal calculi. Both patients had previously been treated unsuccessfully for their stones with shock wave lithotripsy and were referred to our centre for percutaneous nephrolithomy. We were able to avoid surgery in both cases owing to the recognition of uric acid stone composition despite the calculi being visible on CT scout films. | 18,781,215 |
Retrospective assessment of the association between drinking and condom use. | Retrospective reports of the association between drinking and high-risk sexual behavior can be biased by implicit theories of the effects of drinking or may represent post hoc justifications instead of accurate reports of behavior. Using data from a daily diary study, we compared daily reports of condom use when drinking and not drinking with the same participants' reports of these behaviors from a retrospective questionnaire administered after diary collection was complete. Participants included adolescents (n=145), adult sexually transmitted disease clinic clients (n=167), college students (n=145), and men who have sex with men (n=147). All participants reported their alcohol consumption and sexual activity daily for 8 weeks and then completed a retrospective questionnaire about their behavior over the diary period. Participants' retrospective judgments about whether they used condoms more or less when drinking were not significantly related to their behavior as reported in the diary. Fewer than two thirds of the participants were accurate in their recollection of the association of condom use and drinking. Teenagers and men who have sex with men were more likely to retrospectively overestimate the negative effect of alcohol on condom use. Retrospective questions about the association between drinking and condom use were consistent with actual behavior only among people who consistently either never or always used condoms. These individuals correctly reported that drinking had no effect on their condom use. For people whose condom use varies, questions about associations between drinking and sex may be difficult to answer, owing to their conditional nature, and may lead to error. | 18,781,253 |
Effects of elevated CO(2) and O(3) on phenolic compounds in spring wheat and maize leaves. | C(3) crops are generally considered more sensitive than C(4) crops to the elevated CO(2) and O(3), but it is unclear whether the concentrations of phenolic compounds in them are affected. In this paper, an enrichment experiment with open-top chamber was conducted to examine the effects of elevated CO(2), O(3), and their combination on the contents of total phenolic compounds and flavone in the leaves of spring wheat (C(3) crop) and maize (C(4) crop). The results showed for spring wheat, the total phenolic contents in its leaves at jointing stage was significantly higher under elevated CO(2) and/or O(3), with the sequence of CO(2) plus O(3) > O(3) > CO(2) > ambient, while at grain-filling stage, the total phenolic content was lower under CO(2) plus O(3) than under CO(2), O(3), and ambient. The total phenolic content in maize leaves at jointing stage had the similar variation trend with that for wheat, but at grain-filling stage, the total phenolic content was slightly affected by elevated CO(2) and/or O(3). The flavone content in spring wheat leaves was significantly lower under CO(2) and/or O(3) stress at jointing stage, but had lesser difference at grain-filling stage under the stress. The same variation trend was observed in the flavone content in maize leaves at jointing and grainfilling stages, i.e., CO(2) plus O(3) > CO(2) > ambient > O(3). C(3) plant was more sensitive than C(4) plant to the CO(2) and/or O(3) stress. | 18,781,273 |
[Hereditary Alzheimer's disease with amyloid angiopathy caused by amyloid precursor protein locus]. | We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimer's disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimer's dementia. The co-occurrence of CSF changes typical for Alzheimer's disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis. | 18,781,290 |
Histological and ultrastructural evaluation of Leeds-Keio ligament 20 years after implant: a case report. | We were capable of undertaking a histological and ultrastructural evaluation of an intact Leeds-Keio ligament implanted 20 years ago to assess the neoligamentization process inside this artificial ligament. The histological evaluation disclosed a collagen fibrils orientation very close to the structure of a normal anterior cruciate ligament (ACL) where the collagen fibres are multidirectional [Strocchi et al. in J Anat 180(3):515-519, 1992]. On the other hand we found an unimodal distribution of collagen fibrils in the reconstructed ACL. This suggests that even at long-term follow-up stress exerts a variable influence. The multidirectional arrangement of collagen fibres resembles a normal ACL, but the unimodal distribution of fibrils is quite different from those seen in normal tendon and ligaments which tend to have a bimodal peak [Decker et al. in J Submicrosc Cytol Pathol 23:9-21, 1991; Strocchi et al. in J Anat 180(3):515-519, 1992]. Studies based on biopsy suffer from the potential weakness that the specimen may not have been representative of the entire prosthesis. Further long-term studies, possibly with the entire prosthesis and not only a biopsy, would highlight the behaviour and remodelling of this artificial ligament in greater detail and could be important for the development of future generations of artificial ligaments or tissue engineering ACL reconstruction. | 18,781,294 |
[Endophthalmitis after repeated bevacizumab injections]. | Symptoms resembling endophthalmitis developed 1 day after the seventh injection of bevacizumab in a 76-year-old woman with extrafoveal occult choroidal neovascularization in conjunction with age-related macular degeneration. The diagnosis reached was an immune reaction with pseudohypopyon after repeated bevacizumab injections. The condition resolved completely within 5 days under sole administration of corticosteroids. Treatment was then continued with pegaptanib and no further intraocular irritation occurred. | 18,781,307 |
Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. | To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (T(M)), in hepatocellular carcinoma (HCC) patients following resection. The infiltration of TAM and T(M) was assessed by immunohistochemistry in tissue microarray containing 302 HCC specimens. Correlations between TAM/T(M) infiltration and clinicopathologic features, disease-free survival (DFS) and overall survival (OS) were statistically analyzed. High TAM infiltration was associated with both improved DFS (P = 0.0021) and OS (P = 0.0481). Multivariate analysis identified TAM infiltration as independent prognostic factor for DFS (P = 0.004) and OS (P = 0.049). A second analysis clarified the synergistic effect of TAM&T(M) infiltration for DFS (P = 0.004) and OS (P = 0.040). Both TAM infiltration alone and concomitant infiltration of TAM&T(M) are associated with improved DFS/OS, suggesting that TAM could protect HCC patients from recurrence/metastasis and prolong survival by distinct mechanisms. | 18,781,326 |
Blood volume monitoring to adjust dry weight in hypertensive pediatric hemodialysis patients. | The aim of this study was to adjust dry weight by short-term blood volume monitoring (BVM)-guided ultrafiltration and evaluate the effects of optimizing dry weight on blood pressure (BP) control and intradialytic symptoms (IDS) in a group of hypertensive hemodialysis (HD) patients. The study was performed in four sequential phases, each of which lasted for 1 week, on nine hypertensive HD patients (six girls, age 16.9 +/- 3.1 years). In phase I, patients were observed by BVM. In phase II, BVM was used to guide ultrafiltration to adjust dry weight. Antihypertensive drugs were gradually tapered or withheld in phase III, when the patients were hypotensive and/or their IDS increased. In phase IV, this particular weight was maintained without any intervention. Pre- and post-HD body weight, pre-HD, post-HD, 30 min after HD casual BP values, and IDS in each HD session were recorded. The BP was also assessed by 44-h ambulatory BP monitoring (ABPM), which is an ideal method to determine BP changes throughout the interdialytic period at the beginning of phase I and at the end of phase IV. There was a decrease in mean dry weight, all casual systolic BPs, and systolic/diastolic ABPM at the end of the study (all p < or = 0.05). Antihypertensive drugs were stopped in five patients and reduced in two during phase III of the study. The IDS was more frequent (36%) in phase IV than in phase I (16%); however, this increase did not reach statistical significance. The results of this study suggest that short-term BVM guided-ultrafiltration may be a useful tool to diagnose volume overload and to adjust dry weight and, consequently, to achieve a better control of BP in pediatric HD patients. | 18,781,335 |
Medical management of children with primary hypertension by pediatric subspecialists. | Our aim was to characterize medical management of children with primary hypertension (HTN) by pediatric subspecialists. We performed a medical-record review of children < or = 18 years with primary HTN seen at pediatric cardiology or pediatric nephrology clinics at an academic center. Main outcomes were whether treatment decision was in agreement with national guidelines, whether an antihypertensive medication was prescribed, and medication choice. One hundred and eighty children had > or = 1 visit to a pediatric cardiology or nephrology clinic. The majority (83%) of children were pharmacologically managed according to national guidelines. However, only 1/3 children with stage 2 HTN received appropriate antihypertensive therapy from either subspecialty. Only 26 children were prescribed an antihypertensive drug. Children evaluated by pediatric nephrologists were fourfold more likely to receive an antihypertensive than children seen by pediatric cardiologists (29% vs. 7%; p < 0.001). However, all antihypertensive prescriptions were prescribed according to guidelines by both subspecialties. Medical management of children with primary HTN by pediatric cardiologists and pediatric nephrologists is largely consistent with guidelines. However, initiation of appropriate antihypertensive drugs for children with highest severity of HTN is equally poor for both subspecialties. Future studies should explore the factors underlying physicians' reluctance to initiate recommended chronic pharmacologic therapy in children and its associated outcomes. | 18,781,337 |
Sesamin supplementation increases white muscle docosahexaenoic acid (DHA) levels in rainbow trout (Oncorhynchus mykiss) fed high alpha-linolenic acid (ALA) containing vegetable oil: metabolic actions. | The effects of including an equi-mixture of sesamin and episesamin in fish diets based on vegetable oils of different fatty acid composition were examined. Sesamin/episesamin (hereafter named sesamin) was included at 0.58 g/100 g diet. The oil used in the feed was either a mixture of linseed and sunflower oils (6:4, by vol) or 100% linseed oil. Addition of sesamin increased the percentages of docosahexaenoic acid (DHA) in white muscle phospholipid and triacylglycerol fraction by up to 37% but the fatty acids in red muscle and liver were not affected. The expression of the peroxisome proliferator-activated receptor PPARalpha was significantly down regulated in the liver of the fish fed sesamin and mixed oil diet (P < 0.05). Sesamin and episesamin were detected in liver and muscle tissues of the fish that had been fed sesamin. Fish fed sesamin had elevated levels of total cytochrome P450 (CYP) enzymes and EROD activity in the liver, indicating an induction of CYP1A in this tissue. Our conclusion was that supplementation of fish feed with sesamin increased the proportions of DHA in the white muscle. | 18,781,351 |
Fluence-response dynamics of the UV-induced SOS response in Escherichia coli. | Bacteria in nature often suffer sudden stresses, such as ultraviolet (UV) irradiation, nutrient deprivation, and chemotoxins that would cause DNA damage and DNA replication failure, which in turn trigger SOS response. According to the strength and duration of the stress, the SOS system not only repairs DNA damage but also induces mutagenesis, so as to adapt to the changing environment. The key proteins in charge of mutagenesis are UmuD and UmuD'. In this paper, we quantitatively measure the growth rate and cellular levels of proteins UmuD and UmuD' in Escherichia coli after various fluences of UV irradiation. To compare with the experimental observations, an ordinary differential equation model is built to describe the SOS response. Considering the fact that the DNA lesions affect cellular protein production and replication origination, the simulation results fit well with the experimental data. Our results show how the fluence of UV irradiation determines the dynamics of the inducing signal and the mutation frequency of the cell. | 18,781,362 |
Effect of sibutramine HCl on cardiac hERG K+ channel. | Common clinically used drugs block the delayed rectifier K(+) channels and prolong the cardiac action potential duration associated with long QT syndrome. Here, we investigated the mechanism of hERG K(+) channel current (I(hERG)) blockade expressed in HEK-293 cells by sibutramine HCl, a serotonin-norepinephrine reuptake inhibitor. Sibutramine HCl inhibited I (hERG) in a concentration-dependent manner with the half-maximal inhibitory concentration (IC(50)) value of 2.5 microM at -40 mV. I(hERG) inhibition by sibutramine HCl showed weak voltage dependency, but the time-dependence of I(hERG) inhibition was developed relatively rapidly on membrane depolarization. On hERG channel gating for the S6 and pore regions, the S6 residue hERG mutant Y652A and F656A largely reduced the blocking potency of I(hERG), unlike the pore-region mutants T623A and S624A. These results indicate that sibutramine HCl preferentially inhibits the hERG potassium channel through the residue Y652 and F656, in a supratherapeutic concentration should be avoided by patients with high susceptibility for cardiac arrhythmia. | 18,781,376 |
Semiparametric mixed-effects analysis of PK/PD models using differential equations. | Motivated by the use of semiparametric nonlinear mixed-effects modeling on longitudinal data, we develop a new semiparametric modeling approach to address potential structural model misspecification for population pharmacokinetic/pharmacodynamic (PK/PD) analysis. Specifically, we use a set of ordinary differential equations (ODEs) with form dx/dt = A(t)x + B(t) where B(t) is a nonparametric function that is estimated using penalized splines. The inclusion of a nonparametric function in the ODEs makes identification of structural model misspecification feasible by quantifying the model uncertainty and provides flexibility for accommodating possible structural model deficiencies. The resulting model will be implemented in a nonlinear mixed-effects modeling setup for population analysis. We illustrate the method with an application to cefamandole data and evaluate its performance through simulations. | 18,781,382 |
Replication kinetics of Salmonella enteritidis in internal organs of ducklings after oral challenge: a quantitative time-course study using real-time PCR. | This research was undertaken to understand the replication kinetics of Salmonella enteritidis (S. enteritidis) in the internal organs of ducklings after oral challenge over a 2 wk period. A serovar-specific real-time, fluorescence-based quantitative polymerase chain reaction (FQ-PCR) assay was used to detect genomic DNA of S. enteritidis in the blood and the internal organs at different time points respectively. The results showed that the spleen was positive at 12 h post inoculation (PI) and the blood was at 14 h PI. The organism was detected in the liver and heart at 16 h PI, the pancreas and kidney were positive at 20 h PI, and the final organ to show a positive results was the gallbladder at 22 h PI. The copy number of S. enteritidis DNA in each tissue reached a peak at 24 h-36 h PI, with the liver and spleen containing the highest concentration of S. enteritidis. The blood, heart, kidney, pancreas, and gallbladder had low concentrations. S. enteritidis populations began to decrease and were not detectable at 3 d PI, but were still present up to 2 wk for the spleen without causing apparent symptoms. To make the results meaningful, a side-by-side bacteriology method (IFA) was performed. The results of IFA were similar to the FQ-PCR assay. This research provided a significant data for understanding the life cycle of S. enteritidis in the internal organs, and may help to understand the pathogenesis of S.entertidis in the future. | 18,781,393 |
Frequency of Candida spp. in the oral cavity of Brazilian HIV-positive patients and correlation with CD4 cell counts and viral load. | The aim of this study was to evaluate the prevalence of Candida spp., and particularly C. dubliniensis, among oral isolates from Brazilian HIV-positive patients correlating these results with CD4 cell counts and viral load. Forty-five individuals (23 female and 22 male) diagnosed as HIV-positive by ELISA and Western-blot, under anti-retroviral therapy for at least 1 year and without oral candidosis signals were included in the study. The control group was constituted by 45 healthy individuals, matched to the test group in relation to age, gender, and oral conditions. Oral rinses were collected and the identification was performed by phenotypic tests. The existence of C. dubliniensis among the isolates was analyzed using a validated multiplex PCR assay. Candida spp. were detected at significantly higher number in the oral cavity of HIV-positive patients in relation to the controls (P = 0.0008). C. albicans was the most frequently isolated species in both groups. In the HIV group, C. glabrata, C. lipolytica, C. krusei, C. guilliermondii, and C. parapsilosis were also identified. In the control group, we additionally identified C. tropicalis and C. dubliniensis. Two isolates (1.9%, 2/108) from control individuals were identified as C. dubliniensis and this species was not verified in the HIV group. Candida spp. counts were statistically lower (P = 0.0230) in the oral cavity of patients with low viral load (<400 copies/mm(3)). Candida spp. counts did not differ statistically among groups with different levels of CD4 cells counts (P = 0.1068). | 18,781,394 |
[Non-occlusive mesenteric ischemia in a chronic dialysis patient: a case report]. | We report non-occlusive mesenteric ischemia (NOMI) in a patient with hemodialysis-dependent chronic renal failure who presented with acute onset of abdominal pain. On abdominal computed tomography (CT) and CT angiography, pneumatosis intestinalis of the small intestine and mesenteric venous gas were found with patent superior and inferior mesenteric arteries. CT also showed bowel wall thickening with fat stranding at terminal ileum. In emergency laparotomy, necrosis of the terminal ileum over a 4 cm area was identified and the ischemic segment was resected. Histopathological exam was consistent with gangrenous enteritis. Herein, we present exquisite imaging findings of a NOMI case with an overview of related literature. | 18,781,426 |
Dexamphetamine normalises electrophysiological activity in attention deficit-hyperactivity disorder during the Stroop task. | A case study was conducted to investigate whether dexamphetamine enhances interference control in an adult with attention deficit/hyperactivity disorder. Continuous electroencephalography was recorded both on and off dexamphetamine during performance on a Stroop task. An age-, gender- and IQ-matched control also completed the same task. Event related potentials for the control participant revealed a positive potential to incongruent stimuli between 270 and 440 ms, whereas for the participant with attention deficit/hyperactivity disorder off medication, the reverse polarity was observed in a later time window. Following administration of dexamphetamine, however, the event-related potentials for the incongruent condition closely resembled those in the control, suggesting that dexamphetamine successfully normalises electroencephalographic activity. | 18,781,428 |
Asymptomatic motor cortex displacement due to a giant arachnoid cyst. | Cerebral lesions are held to induce plastic changes of the brain. Less well established, however, is how much space-occupying brain lesions may only displace functional representations. In a 66-year-old man we show, by means of functional magnetic resonance imaging and transcranial magnetic stimulation, a profound displacement of the motor cortex due to a large asymptomatic arachnoid cyst. Thus, the chronically compressed brain is capable of sustaining normal brain function without utilizing the potential of cortical plasticity. | 18,781,430 |
Psychogenic memory deficits associated with functional cerebral changes: an FMRI study. | We studied a case of psychogenic amnesia by means of a functional magnetic resonance imaging (fMRI) experiment involving the retrieval of autobiographical memories. The 38-year-old patient was unable to access most of her autobiographical memories from her childhood up to 16 years of age. Compared with the forgotten period, evocation of the normally retrieved memories elicited increased activity in medial temporal and dorso-lateral frontal regions. Evocation of the preserved scattered recollections was associated with bilaterally distributed temporo-parieto-occipital loci of activations. These functional changes seem to support the idea of common mechanisms involved in both organic and psychogenic amnesias. | 18,781,436 |
Exaggerated color perception in a patient with visual form agnosia. | Previous studies on visual form agnosic patients have shown that their color perception is relatively preserved when monochromatic figures are used. However, it is unclear whether their color perception remains normal when figures are composed of two parts in different colors. The results showed that patient X.F. had difficulty in naming both colors when the two colors were placed next to each other, and in discriminating the two-color figure from the figure presented in its larger color. In contrast, X.F. could name the two colors when they were physically separated. These data suggest that X.F. manifests exaggerated color perception, producing a color filling-in effect that may be mediated by her spared early visual area. | 18,781,440 |
Differential reorganization of fusiform gyrus in two types of alexia after stroke. | Lesions affecting the left fusiform gyrus (FG) commonly result in dyslexia and recovery largely depends on efficient reorganization of the reading network. We performed a follow-up fMRI study to elucidate the reorganization patterns of the FG according to the recovery of reading ability in two patients (MH with pure alexia and KM with alexia with agraphia) after stroke involving the left FG. Initially, MH was an effortful letter-by-letter (LBL) reader, and she improved to become a proficient LBL reader. The initial fMRI results showed scattered activation on occipital and ventral temporal cortex during reading, which was localized to right FG in the follow-up study. KM's severe alexia with agraphia did not improve, even after 6 months had passed since the onset of the alexia. The initial and follow-up fMRI results showed no significant activation in the bilateral FG or central higher language areas during word reading. Our results suggest that the reorganization of the FG is different according to the type of alexia and the amount of clinical recovery in each patient. Also, the successful reorganization of the visual component of reading in the right FG is responsible for the recovery of LBL reading in pure alexia. | 18,781,441 |
A feeding education program to prevent mother-to-child transmission of HIV in Haiti. | In Haiti, as in most of the developing world, vertical transmission of HIV from infected mother to infant through postpartum breastfeeding remains a significant mode of transmission. As part of their prevention of mother-to-child transmission program, the Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centers developed a feeding education program in which over 83% of the HIV-positive pregnant women who were eligible to participate, enrolled. Bivariate and adjusted multivariate logistic regression analyses were used to compare feeding choices of the 290 women who participated in the feeding education program to 58 who did not. Of those who participated, 91.7% chose to use replacement formulas for their newborns, while 75.9% of those who did not participate chose replacement feeding. After adjustment for socio-demographic variables, analyses revealed that the no education group was less likely to adopt replacement feeding and more likely to use mixed feeding (OR=0.31, p=0.004; and OR=2.74, p=0.05, respectively). This suggests that a targeted and culturally appropriate education program can be effective in encouraging replacement feeding, even in those countries where breastfeeding is the norm. | 18,781,456 |
Being Bleuler: the second century of schizophrenia. | The aim of this paper is to examine the background to the emblematic psychiatric term, schizophrenia, the historical, cultural and social factors affecting the two men who defined modern psychiatric practice, and anticipate what lies ahead in the next century. The term schizophrenia was created by Swiss psychiatrist Eugene Bleuler and first used on 24 April 1908. The condition was first described by German psychiatrist Emil Kraepelin and called dementia praecox. After a century, it is impossible to think of the practice of psychiatry without schizophrenia. | 18,781,458 |
Predictors of autoimmune disease: autoantibodies and beyond. | Increased emphasis has been placed in recent years on predictive biomarkers to foretell the onset or future course of disease. In autoimmune diseases, autoantibodies have proven to be valuable biomarkers because of their technical sensitivity, specificity, and stability during storage. Their predictive value is limited, however, by their prevalence. At present, predictive studies have utilized long-time evaluation of stable populations, families with one index case or retrospective investigations where large serum repositories are available. Our increasing knowledge of the steps leading from benign autoimmunity to frank autoimmune disease has suggested ways by which subtle genetic differences combined with assessment of the pattern of critical mediators can trace the progression of disease. The new tools of multiplex testing and information handling open opportunities to identify early signposts of disease. | 18,781,467 |
Cross-talk between anti-beta1-adrenoceptor antibodies in dilated cardiomyopathy and Chagas' heart disease. | Anti-beta(1)-adrenoceptor autoantibodies, first described in sera of patients with Chagas' disease, are now well documented in patients with idiopathic dilated cardiomyopathy. The following review summarizes the knowledge we have about the structural basis of receptor-antibody interactions, about their mechanisms of action and about their pathogenicity. While the origin of anti-receptor antibodies with agonist-like activity in Chagas' disease might be ascribed to recognition by anti-parasite antibodies of an epitope, localized on the second extracellular loop of the beta(1)-adrenoceptor, the origin of such antibodies in idiopathic dilated cardiomyopathy remains unknown. The hypothesis of a similar origin for anti-receptor antibodies in both diseases is forwarded. | 18,781,468 |
Recombinant cardiac myosin fragment induces experimental autoimmune myocarditis via activation of Th1 and Th17 immunity. | The specificity and function of T helper (Th) immune responses underlying the induction, progression, and resolution of experimental autoimmune myocarditis (EAM) in A/J mice are unclear. Published data suggest involvement of both Th1 and Th2 responses in EAM; however, the previous inability to assess antigen-specific in vivo and in vitro T-cell responses in cardiac myosin-immunized animals has confounded our understanding of this important model of autoimmune myocarditis. The goal of our study was to develop an alternative model of EAM based on a recombinant fragment of cardiac myosin, in hopes that the recombinant protein will permit measurement of functional T-cell responses that is not possible with purified native protein. A/J mice immunized with a recombinant fragment of cardiac myosin spanning amino acids 1074-1646, termed Myo4, developed severe myocarditis characterized by cardiac hypertrophy, massive mononuclear cell infiltration and fibrosis, three weeks post-immunization. The mice also developed an IgG1 dominant humoral immune response specific for both Myo4 and purified cardiac myosin. The in vitro stimulation of splenocytes harvested from Myo4-immunized animals with Myo4 resulted in cellular proliferation with preferential production of the Th1- and Th17-associated cytokines, IFN-gamma, IL-17, and IL-6, respectively. Production of IL-4 was negligible by comparison. This study describes a new model of EAM, inducible by immunization with a specific fragment of cardiac myosin, from which antigen-specific analyses reveal an importance for both Th1 and Th17 immunity. | 18,781,477 |
Conjugated equine estrogen, raloxifene and arterial stiffness in postmenopausal women. | We analyzed the influence of conjugated equine estrogen (CEE) and raloxifene on arterial stiffness. Sixty-seven healthy, normotensive women 1-10 years into menopause were assigned to receive oral placebo, conjugated equine estrogen 0.625 mg, or raloxifene 60 mg. Arterial stiffness was evaluated by measuring the carotid-femoral and femoral-dorsalis pedis pulse wave velocity (CF PWV, FP PWV). Systolic pressure augmentation index (AI) at the carotid artery was obtained with applanation tonometry. Arterial stiffness was not affected by any treatment regimen: placebo (CF PWV before vs. after: 644 vs. 626 cm/s, p = 0.09; FP PWV before vs. after: 1006 vs. 1012 cm/s,p = 0.77; AI before vs. after = 30 vs. 29%, p = 0.55), CEE (CF PWV before vs. after: 642 vs. 600 cm/s, p = 0.11; FP PWV before vs. after: 952 vs. 971 cm/s, p = 0.66; AI before vs. after: 25 vs. 32%, p = 0.82), and raloxifene (CF PWV before vs. after: 636 vs. 601 cm/s, p = 0.12; FP PWV before vs. after: 964 vs. 941 cm/s, p = 0.62; AI before vs. after: 25 vs. 25%, p = 0.65). A correlation occurred between basal stiffness and the degree of reduction in indexes measured, indicating that the higher the basal stiffness, the greater the degree of reduction, particularly in the CEE group: CF PWV (r = - 0.602, p = 0.001); FP PWV (r = - 0.455, p = 0.022); AI (r = - 0.410, p = 0.042). Conjugated equine estrogen and raloxifene do not seem to affect arterial stiffness of healthy normotensive women less than 10 years since menopause. Reduction in arterial stiffness seems related to its basal level. | 18,781,483 |
Restless legs syndrome among women: prevalence, co-morbidity and possible relationship to menopause. | Restless legs syndrome (RLS) is a common neurological movement disorder with a female preponderance and an increasing prevalence with age. During the menopausal transition, sleep is affected. Prior studies suggest that female hormones are associated with the clinical manifestation of RLS. A random sample of 5000 women aged 18-64 years was selected from the general Swedish population. They were sent questions on RLS, general health, sleep problems, reproductive health and menopausal state. The response rate was 70.3%; 15.7% of the women were diagnosed with RLS. Prevalence increased with age. RLS subjects more often had symptoms of affected sleep and depressed mood. Co-morbidity with heart disease was more common among RLS subjects, whereas hypertension and diabetes mellitus were not. There was a strong association between vasomotor symptoms and RLS but no statistical relationship between use of hormone replacement therapy, postmenopausal state and RLS. The prevalence of RLS among Swedish women is high. RLS sufferers more often suffered from depression and heart disease, whereas no such associations were noted for diabetes or hypertension. We found an increased prevalence of RLS among women with vasomotor symptoms (night sweats) during the menopausal transition but not among women using hormone replacement therapy. | 18,781,488 |
Infant hearing loss in South Africa: age of intervention and parental needs for support. | Hearing loss is referred to as the silent, overlooked epidemic in developing countries, and data reporting the mean age of diagnosis and intervention is virtually non-existent due to limited systematic or routine screening programs. The objective of this paper is to present findings of recent practice in early diagnosis and intervention services in an urban South African context, with specific reference to parental needs for support. Data was collected by means of questionnaire surveys for 54 parents of children with congenital or early-onset hearing loss, followed by focus group discussions conducted with 10 parents. The results of this study indicate the mean age of diagnosis to be 23 months (+/-18 SD), the mean age of initial hearing-aid fitting to be 28 months (+/-19 SD), and the mean age of enrollment into an early intervention program to be 31 months (+/-19 SD). In addition, results signify that this diverse and challenging population of parents of young hearing-impaired children largely depends on the ongoing support, guidance, and commitment of the pediatric audiologist. | 18,781,511 |
Statistical assessment of analytical method transfer. | Analytical method transfer is an important part of analytical method development and maintenance. The current common practice of analytical method transfer is based on the equivalence of the means between the original laboratory and the receiving laboratory. However, for some assays the most scientifically sound approach would be to show the equivalency of individual sample readings between the two laboratories. In this study, statistical approaches such as limit of agreement, total deviation index, and tolerance interval approach to address individual equivalence between laboratories are discussed. Using a tolerance interval approach that is equivalent to the two one-sided hypothesis testing is proposed. These approaches are compared with each other and also with the mean equivalence approach on their statistical properties. Examples are presented to illustrate each analysis approach and the comparisons. | 18,781,532 |
Design and analysis of analytical method transfer studies. | A method transfer study is designed to successfully transfer technology from an origination laboratory to a destination laboratory. Following quality by design principles, a method transfer study is part of an analytical process to confirm the repeatability and ruggedness of the technology to be transferred. The primary objective of the study and statistical analysis is to demonstrate equivalence between laboratory mean responses. Additional information demonstrating the consistency of analysts within laboratories and the proficiency of each laboratory and analyst to reproduce the expected result can be obtained. Three representative study designs are discussed and an example is presented. | 18,781,533 |
[Psychological consequences of perinatal loss in subsequent pregnancies--a comparative study]. | Pregnancies after perinatal loss occur often. However, little is known about the need of secondary psychological prevention in these instances. Therefore we investigated psychological disorder and distress during the subsequent pregnancy after perinatal loss. We compared psychological symptoms in pregnant women with and without previous perinatal loss. Pregnant women in the PL-group did not suffer more from depression, anxiety and other psychological distress than women without perinatal loss. Nearly a third of the women in the PL-group were classified as unresolved with regard to their mental representation of attachment indicating that their mourning process was still not completed. Women who have suffered from perinatal loss do not score higher on depression, anxiety or general psychopathology during subsequent pregnancies than women without loss experience. Only a minority of women, who have suffered from loss show ongoing signs of unresolved mourning. However, in order to detect criteria for the identification of those who might be at risk during subsequent pregnancies studies with larger samples size are necessary. | 18,781,543 |
[Differential indication of inpatient and day clinic treatment in psychosomatics]. | Aim of the "DINSTAP"-study is to identify criteria that are of importance for a decision between inpatient or day clinic treatment in patients that are usually admitted to psychosomatic clinics in Germany. 299 inpatient and 268 day clinic treatment episodes from 10 clinics were included in the study. Next to basic data and diagnosis, severity of symptoms and impairment were evaluated (pre, post). A questionnaire was developed which includes aspects that are relevant for differential indication according to clinical experts. This questionnaire was filled out before admission. First results show that patients in both treatment settings were comparable concerning impairment at intake. Inpatients showed better improvement (SCL-90-R, GAF) over the course of treatment. Aspects like the necessity of relief from everyday tasks or a daily "training situation" at home allowed a prediction of therapist's decision for inpatient or day clinic treatment. Further detailed analyses are planned to answer the question of differential indication more comprehensively. | 18,781,542 |
Modified chitosans for oral drug delivery. | The cationic polysaccharide chitosan has been extensively studied for oral drug delivery. In recent years, chemically modified chitosans developed in order to improve the properties of chitosan for oral drug delivery have gained increasing attention. Representatives of these novel polymers are trimethyl-chitosans, thiolated chitosans, carboxymethyl chitosan and derivatives, hydrophobic chitosans, chitosan succinate and phthalate, PEGylated chitosans and chitosan-enzyme inhibitor conjugates. Besides their use for oral delivery of therapeutic peptides and proteins, they have recently been evaluated regarding their potential for the delivery of other substance classes, including genes and efflux pump substrates. Within the current review, various modified chitosan derivatives, their properties and synthesis are discussed. | 18,781,621 |
Improving powder flow properties of citric acid by crystal hydration. | A batch of poorly flowing citric acid anhydrate was exposed to 69.9% relative humidity to prepare pure monohydrate with nearly identical particle size and morphology but different surface properties. Flow properties of the powders were tested using a ring shear cell. Results show the hydration can significantly improve flow properties of anhydrous citric acid. | 18,781,624 |
Oxidation of methionine residue at hydrophobic core destabilizes p53 tetrameric structure. | The tumor suppressor protein p53 is a tetrameric phosphoprotein that induces cell cycle, development, and differentiation by regulating the expression of target genes. The tetramerization of p53 is essential for its tumor suppressor functions. It has been known that oxidation of proteins affects their structure and function. A methionine residue (Met340) is located at the hydrophobic core in p53 tetramerization domain. Here, we demonstrated that Met340 residue can be oxidized to methionine sulfoxide under oxidative conditions and investigated effects of the oxidation of p53 tetramerization domain on its stability and oligomerization state by CD measurement and gel filtration. The oxidation of Met340 drastically induced destabilization of the p53 tetramer by 22.8 kJ/mol of DeltaDeltaG(Tm), while retaining the identical conformation as that of the wild-type peptide. Trypsin digestion experiments also showed that oxidation of Met340 allowed the peptide to form locally loose structure and become more sensitive to enzyme degradation. The tetrameric structure may be destabilized because the oxidation of Met340 induces charge repulsion and/or steric hindrance between the sulfoxide groups. These results taken together suggested that oxidation of methionine residues in the p53 protein might be one of the inactivation mechanisms of p53 transcriptional function under conditions of oxidative stress. | 18,781,628 |
The impact of protein concentration on mannitol and sodium chloride crystallinity and polymorphism upon lyophilization. | The effect of protein concentration, in the range of 0-26 mg/mL for two Fc-fusion proteins, on the crystallinity and polymorphism of mannitol and sodium chloride in a lyophilized model formulation was examined. Mannitol hydrate levels were quantified based on moisture data and correlated to the X-ray diffraction peak area. In all formulation conditions, sodium chloride did not crystallize in samples with >44% total amorphous content. As protein concentration increased through the range of 1-5 mg/mL prior to lyophilization, beta-mannitol decreased in amount, becoming undetectable at protein concentrations above 5 mg/mL. Conversely, delta-mannitol increased as a function of protein concentration, reaching a maximum level at approximately 5 mg/mL protein. Above 10 mg/mL protein, mannitol crystallization was increasingly inhibited. Sucrose control vials showed higher levels of mannitol hydrate than either model protein. Both proteins behaved comparably with respect to mannitol crystallinity and polymorphism despite significant differences in molecular weight. Because of the differences between protein and sucrose control samples, protein concentration must be taken into consideration when assessing the lyophilization of mannitol containing solutions. | 18,781,637 |
Annual assessment spirometry, plethysmography, and gas transfer in cystic fibrosis: do they predict death or transplantation. | The long- and short-term prognostic value of pediatric spirometry, plethysmography, and gas transfer measurements in cystic fibrosis (CF) were assessed. Two hundred ninety-eight children with CF and >or=4 annual assessment lung function measurements at a single institution were analyzed in mid childhood. Long-term outcome was death or lung transplantation (D/T) before 2007. Short-term outcome was forced expired volume in one second (FEV(1)) z-score 1 year after the previous lung function measurements. 26/298 had a D/T outcome at median 19.5 years. A zFEV(1) < -2 aged 8 years had a positive predictive value of 67% (sensitivity 67%) for D/T in those homozygous for DeltaF508 but zFEV(1) at older ages and all genotypes was unhelpful. The ratio of residual volume to total lung capacity z-score could also predict a few D/T individuals when zFEV(1) was normal in mid childhood. Most other lung function measurements were not helpful. Matching D/T with alive groups for year of birth left prognostic utility unchanged. Only current zFEV(1) could significantly predict zFEV(1) 1 year hence (56% variability explained, P < 0.00001); no other lung function, gender, age or nutrition factor was significant. The value of routine plethysmography and gas transfer measurements in CF is questionable in CF management. Detecting abnormal spirometry even at age 8 years may be too late to affect long-term outcome. | 18,781,653 |
Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease. | The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG. | 18,781,672 |
Molecular mechanisms underlying levodopa-induced dyskinesia. | Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease, chronic therapy with this pharmacological compound initiates a complex cascade of cellular and molecular downstream effects resulting in the development of abnormal involuntary movements. The precise mechanisms underlying the development of levodopa induced dyskinesia, however, are far from being completely elucidated. In the present review, we will describe changes in long-term synaptic excitability following dopamine (DA) denervation and long-term levodopa treatment leading to abnormal involuntary movements. In particular, we will address the role of both DA D1 receptors and NMDA glutamate receptors in the induction and maintenance of dyskinesia and abnormal synaptic plasticity. We will also describe the possible interaction between these two receptors in the pathophysiology of dyskinesia taking the advantage of the existing knowledge concerning the mechanisms underlying drug abuse. This latter pathophysiological condition, in fact, seems to share several biochemical transduction pathways with those implicated in levodopa-induced dyskinesia. Finally, we will briefly discuss the possible implication of A2A adenosine receptors in long-term motor complications of levodopa therapy and focus on the interaction between A2A and D2 receptors. Future studies are required to understand how the interaction between these various biochemical steps converge to produce a long-term change in neuronal excitability within the basal ganglia leading to abnormal involuntary movements following levodopa treatment in the DA-denervated state. | 18,781,674 |
Effect of enzyme supplementation at moderate cellulase loadings on initial glucose and xylose release from corn stover solids pretreated by leading technologies. | Moderate loadings of cellulase enzyme supplemented with beta-glucosidase were applied to solids produced by ammonia fiber expansion (AFEX), ammonia recycle (ARP), controlled pH, dilute sulfuric acid, lime, and sulfur dioxide pretreatments to better understand factors that control glucose and xylose release following 24, 48, and 72 h of hydrolysis and define promising routes to reducing enzyme demands. Glucose removal was higher from all pretreatments than from Avicel cellulose at lower enzyme loadings, but sugar release was a bit lower for solids prepared by dilute sulfuric acid in the Sunds system and by controlled pH pretreatment than from Avicel at higher protein loadings. Inhibition by cellobiose was observed to depend on the type of substrate and pretreatment and hydrolysis times, with a corresponding impact of beta-glucosidase supplementation. Furthermore, for the first time, xylobiose and higher xylooligomers were shown to inhibit enzymatic hydrolysis of pure glucan, pure xylan, and pretreated corn stover, and xylose, xylobiose, and xylotriose were shown to have progressively greater effects on hydrolysis rates. Consistent with this, addition of xylanase and beta-xylosidase improved performance significantly. For a combined mass loading of cellulase and beta-glucosidase of 16.1 mg/g original glucan (about 7.5 FPU/g), glucose release from pretreated solids ranged from 50% to75% of the theoretical maximum and was greater for all pretreatments at all protein loadings compared to pure Avicel cellulose except for solids from controlled pH pretreatment and from dilute acid pretreatment by the Sunds pilot unit. The fraction of xylose released from pretreated solids was always less than for glucose, with the upper limit being about 60% of the maximum for ARP and the Sunds dilute acid pretreatments at a very high protein mass loading of 116 mg/g glucan (about 60 FPU). | 18,781,688 |
A population analysis of VEGF transgene expression and secretion. | The induction of therapeutic angiogenesis with gene therapy approaches has received considerable interest and some limited clinical success. A major drawback to this approach is a lack of understanding of the pharmacokinetics of therapeutic protein delivery. This has become increasingly more relevant as recent studies have illustrated a defined therapeutic window for angiogenic protein secretion into the local microenvironment. For cell based gene therapies, with cells widely distributed throughout the tissue, this implies that any individual cell must attain a specific secretion rate to produce a local angiogenic response. Here we report a reproducible technique enabling the study of growth factor secretion from individual cells following transient plasmid transfection. We demonstrate significant variability in single cell vascular endothelial growth factor (VEGF) secretion with the majority of total protein secretion arising from a small subpopulation of transfected cells. We demonstrate that VEGF secretion is linearly correlated to intracellular plasmid copy number and protein secretion does not appear to reach saturation within the cell population. The selection of gene therapy approaches that optimize individual cell secretion profiles may be essential for the development of effective gene therapies. | 18,781,692 |
Sensitive liquid chromatography tandem mass spectrometry method for the quantification of Quetiapine in plasma. | A sensitive high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of quetiapine in rat plasma. Following liquid-liquid extraction, the analyte was separated using a gradient mobile phase on a reverse-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M + H]+ ions, m/z 384 to m/z 221 for quetiapine and m/z 327 to m/z 270 for the internal standard. The assay exhibited a linear dynamic range of 0.25-500 ng/mL for quetiapine in rat plasma. The lower limit of quantification was 0.25 ng/mL with a relative standard deviation of less than 7%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The validated method was successfully used to analyze rat plasma samples for application in pre-clinical pharmacokinetic studies. This method in rodent plasma could be adapted for quetiapine assay in human plasma. | 18,781,706 |
Coexistence of two aggregation modes in exotic liquid-crystalline superstructure: systematic maximum entropy analysis for cubic mesogen, 1,2-bis(4'-n-alkoxybenzoyl)hydrazine [BABH(n)]. | Structure of a complex superstructure self-organized by thermotropic mesogen, 1,2-bis(4'- n-alkoxybenzoyl)hydrazine [BABH(n), where n is the number of carbon atoms in an alkoxy chain] was studied while paying special attention to the structure at the molecular level. Maximum entropy (MEM) analysis revealed that the molecular cores form two kinds of aggregates: Jungle gym with 3-fold junctions roughly on P minimal surface and spherical shells. | 18,781,713 |
A polarizable force field for computing the infrared spectra of the polypeptide backbone. | The shapes of the amide bands in the infrared (IR) spectra of proteins and peptides are caused by electrostatically coupled vibrations within the polypeptide backbone and code the structures of these biopolymers. A structural decoding of the amide bands has to resort to simplified models because the huge size of these macromolecules prevents the application of accurate quantum mechanical methods such as density functional theory (DFT). Previous models employed transition-dipole coupling methods that are of limited accuracy. Here we propose a concept for the computation of protein IR spectra, which describes the molecular mechanics (MM) of polypeptide backbones by a polarizable force field of "type II". By extending the concepts of conventional polarizable MM force fields, such a PMM/II approach employs field-dependent parameters not only for the electrostatic signatures of the molecular components but also for the local potentials modeling the stiffness of chemical bonds with respect to elongations, angle deformations, and torsions. Using a PMM/II force field, the IR spectra of the polypeptide backbone can be efficiently calculated from the time dependence of the backbone's dipole moment during a short (e.g., 100 ps) MD simulation by Fourier transformation. PMM/II parameters are derived for harmonic bonding potentials of amide groups in polypeptides from a series of DFT calculations on the model molecule N-methylacetamide (NMA) exposed to homogeneous external electric fields. The amide force constants are shown to vary by as much as 20% for relevant field strengths. As a proof of principle, it is shown that the large solvatochromic effects observed in the IR spectra of NMA upon transfer from the gas phase into aqueous solution are not only excellently reproduced by DFT/MM simulations but are also nicely modeled by the PMM/II approach. The tasks remaining for a proof of practice are specified. | 18,781,720 |
Marangoni flow of Ag nanoparticles from the fluid-fluid interface. | Fluid flow is observed when a volume of passivated Ag nanoparticles suspended in chloroform is mixed with a water/ethanol (v/v) mixture containing acidified 11-mercaptoundecanoic acid. Following mechanical agitation, Ag nanoparticles embedded in a film are driven from the organic-aqueous interface. A reddish-brown colored film, verified by transmission electron microscopy to contain uniformly dispersed Ag nanoparticles, is observed to spontaneously climb the interior surface of an ordinary, laboratory glass vial. This phenomenon is recorded by a digital video recorder, and a measurement of the distance traveled by the film front versus time is extracted. Surface (interfacial) tension gradients due to surfactant concentration, temperature, and electrostatic potential across immiscible fluids are known to drive interface motion; this well-known phenomenon is termed Marangoni flow or the Marangoni effect. Experimental results are presented that show the observed mass transfer is dependent on an acid surfactant concentration and on the volume fraction of water in the aqueous phase, consistent with fluid flow induced by interfacial tension gradients. In addition, an effective desorption rate constant for the Marangoni flow is measured in the range of approximately 0.01 to approximately 1 s(-1) from a fit to the relative film front distance traveled versus time data. The fit is based on a time-dependent expression for the surface (interface) excess for desorption kinetics. Such flow suggests that purposeful creation of interfacial tension gradients may aid in the transfer of 2- and 3-dimensional assemblies, made with nanostructures at the liquid-liquid interface, to solid surfaces. | 18,781,724 |
Thermally induced magnetic anomalies in solvates of the bis(hexafluoroacetylacetonate)copper(II) complex with pyrazolyl-substituted nitronyl nitroxide. | We succeeded in synthesizing of a whole family of isostructural solvates of the copper(II) hexafluoroacetylacetonate complex with pyrazolyl-substituted nitronyl nitroxide (L): Cu(hfac)2L x 0.Solv. The main feature inherent in nature of Cu(hfac)2L x 0.5 Solv single crystals is their incredible mechanical stability and ability to undergo reversible structural rearrangements with temperature variation, accompanied by anomalies on the mu(eff(T)) dependence. Structural investigation of the complexes over a wide temperature range before and after the structural transition and the ensuing magnetic phase transition showed that the spatial peculiarities of the solvent molecules incorporated into the solid govern the character of the mu(eff(T)) dependence and the temperature region of the magnetic anomaly. Thus, doping of crystals with definite solvent molecules could be used as an efficient method of control over the magnetic anomaly temperature (T(a)). The investigation of this special series of crystals has revealed the relationship between the chemical step and the magnetic properties. It was shown that "mild" modification of T(a) for Cu(hfac)2L x 0.5 Solv required a much smaller structural step than the typical change of one -CH2- fragment in a homologous series in organic chemistry. Quantum-chemical calculations with the use of X-ray diffraction data allowed us to trace the character of changes in the exchange interaction parameters in the range of the phase transition. In the temperature range of the phase transition, the exchange parameter changes substantially. The gradual decrease in the magnetic moment, observed in most experiments during sample cooling to T(a), is the result of the gradual increase in the fraction of the low-temperature phase in the high-temperature phase. | 18,781,735 |
Unsymmetrical platinum(II) phosphido derivatives: oxidation and reductive coupling processes involving platinum(III) complexes as intermediates. | Reaction of the trinuclear [NBu 4] 2[(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(R F) 2] ( 1, R F = C 6F 5) with HCl results in the formation of the unusual anionic hexanuclear derivative [NBu 4] 2[{(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(mu-Cl)} 2] ( 4, 96 e (-) skeleton) through the cleavage of two Pt-C 6F 5 bonds. The reaction of 4 with Tl(acac) yields the trinuclear [NBu 4][(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(acac)] ( 5, 48 e (-) skeleton), which is oxidized by Ag (+) to form the trinuclear compound [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(acac)][ClO 4] ( 6, 46 e (-) skeleton) in mixed oxidation state Pt(III)-Pt(III)-Pt(II), which displays a Pt-Pt bond. The reduction of 6 by [NBu 4][BH 4] gives back 5. The treatment of 6 with Br (-) (1:1 molar ratio) at room temperature gives a mixture of the isomers [(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-Br)Pt(mu-PPh 2) 2Pt(acac)], having Br trans to R F ( 7a) or Br cis to R F ( 7b), which are the result of PPh 2/C 6F 5 reductive coupling. The treatment of 5 with I 2 (1:1 molar ratio) yields the hexanuclear [{(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-I)Pt(mu-PPh 2) 2Pt(mu-I)} 2] ( 8, 96 e (-) skeleton), which is easily transformed into the trinuclear compound [(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-I)Pt(mu-PPh 2) 2Pt(I)(PPh 3)] ( 9, 48 e (-) skeleton). Reaction of [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(NCMe) 2] ( 10) with I 2 at 213 K for short reaction times gives the trinuclear platinum derivative [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(I) 2] ( 11, 46e skeleton) in mixed oxidation state Pt(III)-Pt(III)-Pt(II) and with a Pt-Pt bond, while the reaction at room temperature and longer reactions times gives 8. The structures of the complexes have been established by multinuclear NMR spectroscopy. In particular, the (195)Pt NMR analysis, carried out also by (19)F- (195)Pt heteronuclear multiple-quantum coherence, revealed an unprecedented shielding of the (195)Pt nuclei upon passing from Pt(II) to Pt(III). The X-ray diffraction structures of complexes 4, 5, 6, 9, and 11 have been studied. A detailed study of the relationship between the complexes has been carried out. | 18,781,738 |
The difference a Se makes? Oxygen-tolerant hydrogen production by the [NiFeSe]-hydrogenase from Desulfomicrobium baculatum. | Protein film voltammetry studies of the [NiFeSe]-hydrogenase from Desulfomicrobium baculatum show it to be a highly efficient H2 cycling catalyst. In the presence of 100% H2, the ratio of H2 production to H2 oxidation activity is higher than for any conventional [NiFe]-hydrogenases (lacking a selenocysteine ligand) that have been investigated to date. Although traces of O2 (<< 1%) rapidly and completely remove H2 oxidation activity, the enzyme sustains partial activity for H2 production even in the presence of 1% O2 in the atmosphere. That H2 production should be partly allowed, whereas H2 oxidation is not, is explained because the inactive product of O2 attack is reductively reactivated very rapidly, but this requires a potential that is almost as negative as the thermodynamic potential for the 2H(+)/H2 couple. The study provides further encouragement and clues regarding the feasibility of microbial/enzymatic H2 production free from restrictions of anaerobicity. | 18,781,742 |
Oxidation of a mustard gas analogue using an aldehyde/O2 system catalyzed by V-doped mesoporous silica. | Vanadium-doped mesoporous silica was shown to be an effective heterogeneous catalyst for the oxidation of a mustard gas analogue, 2-chloroethyl ethyl sulfide (CEES), in the presence of an aldehyde and molecular oxygen. The oxidation was shown to involve a radical mechanism, which was indicated by the appearance of an induction period when the reaction occurred in the presence of a free radical scavenger. The reaction was initially selective for the oxidation of CEES to the sulfoxide, CEESO, although oxidation of the sulfoxide to the sulfone occurred once all the CEES had been oxidized. Chemical analysis indicated that V species did not leach from the silica support when the reaction was performed in the fluorinated solvent HFE-7100. | 18,781,745 |
In situ observation of the internal structure and composition of biomineralized Emiliania huxleyi calcite by solid-state NMR Spectroscopy. | Biomineralization, particularly the formation of calcium carbonate structures by organisms under ambient conditions, is of vast fundamental and applied interest. Organisms finely control all aspects of the formation of the biomaterials: composition, polymorph, morphology, and macroscopic properties. While in situ molecular-level characterization of the resulting biominerals is a formidable task, solid-state magic angle spinning NMR is one of the most powerful analytical techniques for this purpose. It is employed in this study to elucidate the structure and composition of biogenic calcite formed by Emiliania huxleyi, a unicellular alga distinguished by its exquisitely sculptured calcite cell coverings known as coccoliths. Strain 371 (CCMP) was grown and harvested from (15)N- and (13)C-enriched growth medium, with biosynthetic labeling to enhance the sensitivity of the NMR measurements. Crystalline and interfacial calcite environments were selectively probed using direct and indirect (cross-polarized) (13)C excitation, respectively. Different crystalline environments, in particular structural defect sites at concentrations of up to 1.4% with P and N moieties incorporated, were identified using (13)C rotational-echo double-resonance (REDOR) NMR. REDOR-derived geometrical constraints show that the P and N atoms at the defect sites are 3.2 and 2.3 (+/-0.2) A apart from a crystalline carbon carbonate. The phosphorus and nitrogen moieties within the biogenic calcite are identified as small, non-protonated moieties, attributed to inorganic ions such as PO4(3-) and NO3(-). The carbonates adjacent to these defects are chemically indistinguishable from bulk crystalline carbonates, yet their immediate environments experience reduced rigidity, as reflected by substantial T1((13)CO3(2-)) shortening. Interfacial carbonates, on the other hand, reside in structurally/chemically perturbed environments, as reflected by heterogeneous line broadening. This study is the first to directly unravel evidence on the incorporation of P/N moieties as structural defects within E. huxleyi biogenic calcite, and on the state of the adjacent crystalline carbonates. | 18,781,749 |
Solution structure of a peptide nucleic acid duplex from NMR data: features and limitations. | This paper describes the results of a 1D and 2D NMR spectroscopy study of a palindromic 8-base pair PNA duplex GGCATGCC in H2O and H2O-D2O solutions. The (1)H NMR peaks have been assigned for most of the protons of the six central base pairs, as well as for several amide protons of the backbone. The resulting 36 interbase and base-backbone distance restraints were used together with Watson-Crick restraints to generate the PNA duplex structure in the course of 10 independent simulated annealing runs followed by restrained molecular dynamics (MD) simulations in explicit water. The resulting PNA structures correspond to a P-type helix with helical parameters close to those observed in the crystal structures of PNA. Based on the current limited number of restraints obtained from NMR spectra, alternative structures obtained by MD from starting PNA models based on DNA cannot be ruled out and are also discussed. | 18,781,753 |
Development of a capillary electrophoresis-based immunoassay with laser-induced fluorescence for the detection of carbaryl in rice samples. | A capillary electrophoresis-based competitive immunoassay (CEIA) with a laser-induced fluorescence (LIF) detector for the determination of carbaryl was developed. The method was based on the competitive reactions between fluorescently labeled carbaryl tracer (Ag*) and free carbaryl (Ag) with a limited amount of anticarbaryl antibody (Ab), and the relative amounts of each were separated and determined by capillary electrophoresis (CE) with an LIF detector. Using CEIA, equilibrium was reached in 30 min, and the analytical results were obtained within a further 8 min. The linear range and the detection limit for carbaryl were 0.16-50 ng/mL and 0.05 ng/mL, respectively. The sensitivity of this CEIA with an LIF detector was almost 14 times greater than that of ELISA, which used the same immuno-reagents. The method was also applied to the analysis of carbaryl in rice with rapid and simple sample pretreatment. The method is thus proposed as a fast and sensitive assay for the detection of carbaryl. | 18,781,759 |
Algicidal activity of stilbene analogues. | Continuing our search for natural product and natural product-based compounds for the control of off-flavor in catfish, 29 stilbene analogues were synthesized and evaluated for algicidal activity against the 2-methylisoborneol (MIB)-producing cyanobacterium Oscillatoria perornata. The cis and trans isomers of 4-(3,5-dimethoxystyryl)aniline showed moderate and selective algicidal activity toward O. perornata with the lowest observed inhibitory concentration and lowest complete inhibition concentrations of 10 muM. This is the first report on selective stilbene algicidal activity toward a MIB-producing cyanobacteria species. | 18,781,760 |
Doubly responsive polymer-microgel composites: rheology and structure. | Mixtures of alkali swellable microgels and linear PNIPAm chains exhibit doubly responsive properties both with pH and temperature. Below the lower critical solution temperature (LCST), the linear chains of PNIPAm are soluble and increase the osmotic pressure outside the microgels, which causes them to deswell. Above the LCST, the PNIPAm chains become insoluble and form spherical colloidal particles confined between the microgels that subsequently reswell. The swelling and deswelling of the microgels change the rheological properties of the composites, providing a unique way to tune the elasticity of the composites with temperature. The structure of the composites above the LCST is studied using multiple light scattering and fluorescence confocal microscopy. The phase separation of PNIPAm above the LCST is strongly affected by the confinement of the PNIPAm chains between the microgels. | 18,781,781 |
Local concentration of gel phase domains in supported lipid bilayers under light irradiation in binary mixture of phospholipids doped with dyes for photoinduced activation. | Recently, lipid bilayers supported on solid substrates are considered to offer potential as biological devices utilizing biological membranes and membrane proteins. In particular, artificially patterned supported bilayers hold great promise for the development of biological devices. In this study, we show control of the formation and location of phase-separated domain structures by light irradiation for gel phase and liquid-crystalline phase separation structures in a DMPC-DOPC binary lipid bilayer tagged with dye molecules on SiO2/Si substrates. Upon light irradiation, the gel phase domain structures disappeared from the phase-separated bilayers. This disappearance indicates that the light irradiation causes a local increase in the temperature of the lipid bilayer. In this disappearance phenomenon, the photoinduced activation of dye lipids, e.g. fluorescent lipids, is considered to play an important role, since the same phenomenon does not occur in lipid bilayers that have a low concentration of dye lipids. Thus, the local increase in temperature is propagated by light absorption of the dye lipid and subsequent photoinduced activation of nonradiative molecular vibrations. Subsequent interruption of the photoinduced activation for molecular motion allowed the gel phase domain structures to precipitate and grow again. Moreover, the domain area fraction remaining after the photoinduced activation was higher than that before the photoinduced activation. This result indicates that the local increase in temperature propagated by dye-excitation enhances formation of the gel phase domains. By utilizing this phenomenon, we could preferentially induce formation of domain structures within the light-irradiated regions. This technique could be the basis for a new patterning technique based on domain structures. Moreover, these domain structure patterns can be eliminated by increasing the temperature, allowing rewritable patterning. | 18,781,791 |
Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry. | Ubiquitination regulates a host of cellular processes by labeling proteins for degradation, but also by functioning as a regulatory, nonproteolytic posttranslational modification. Proteome-wide strategies to monitor changes in ubiquitination profiles are important to obtain insight into the various cellular functions of ubiquitination. Here we describe generation of stable cell lines expressing a tandem hexahistidine-biotin tag (HB-tag) fused to ubiquitin for two-step purification of the ubiquitinated proteome under fully denaturing conditions. Using this approach we identified 669 ubiquitinated proteins from HeLa cells, including 44 precise ubiquitin attachment sites on substrates and all seven possible ubiquitin chain-linkage types. To probe the dynamics of ubiquitination in response to perturbation of the ubiquitin/proteasome pathway, we combined ubiquitin profiling with quantitative mass spectrometry using the stable isotope labeling with amino acids in cell culture (SILAC) strategy. We compared untreated cells and cells treated with the proteasome inhibitor MG132 to identify ubiquitinated proteins that are targeted to the proteasome for degradation. A number of proteasome substrates were identified. In addition, the quantitative approach allowed us to compare proteasome targeting by different ubiquitin chain topologies in vivo. The tools and strategies described here can be applied to detect changes in ubiquitination dynamics in response to various changes in growth conditions and cellular stress and will contribute to our understanding of the ubiquitin/proteasome system. | 18,781,797 |
Wafer-scale reduced graphene oxide films for nanomechanical devices. | We report a process to form large-area, few-monolayer graphene oxide films and then recover the outstanding mechanical properties found in graphene to fabricate high Young's modulus (<E> =185 GPa), low-density nanomechanical resonators. Wafer-scale films as thin as 4 nm are sufficiently robust that they can be delaminated intact and resuspended on a bed of pillars or field of holes. From these films, we demonstrate radio frequency resonators with quality factors (up to 4000) and figures of merit ( f x Q>10(11)) well exceeding those of pure graphene resonators reported to date. These films' ability to withstand high in-plane tension (up to 5 N/m) as well as their high Q-values reveals that film integrity is enhanced by platelet-platelet bonding unavailable in pure graphite. | 18,781,807 |
Chromatin-modifying enzymes as therapeutic targets--Part 1. | Disease pathogenesis may result from genetic alterations and/or a more diverse group of epigenetic changes. While events such as DNA methylation are well established, there is significant interest in nucleosome remodeling, RNA interference and histone modifications, as mechanisms that underlie epigenetic effects. While genetic mutations are permanent, epigenetic changes can be transitory. The potential to reverse epigenetic changes has led to the development of therapeutic strategies targeting chromatin-modifying enzymes. To review the roles of chromatin-modifying enzymes in gene regulation and to highlight their potentials as therapeutic targets. This review is based on recently published literature and online resources. This paper focuses on enzymes responsible for histone acetylation, deacetylation, methylation and demethylation, and their potential as targets for epigenetic therapies. A subsequent paper will do the same for enzymes responsible for histone phosphorylation, ubiquitylation, SUMOylation and poly-ADP-ribosylation as well as ATP-dependent nucleosome remodeling. | 18,781,828 |
Inferring ancestral gene orders for a family of tandemly arrayed genes. | Tandemly arrayed genes (TAG) constitute a large fraction of most genomes and play important biological roles. They evolve through unequal recombination, which places duplicated genes next to the original ones (tandem duplications). Many algorithms have been proposed to infer a tandem duplication history for a TAG cluster. However, the presence of different transcriptional orientations in many clusters highlights the fact that processes such as inversions also contribute to their evolution. Moreover, existing algorithms are restricted to the study of TAGs evolution in a single species (only paralogous genes are considered). To circumvent these limitations, we consider an evolutionary model for TAGs involving duplication, gene loss, inversion, and speciation events. A general framework to infer ancestral gene orders that minimize the number of inversions in the whole evolutionary history is presented. At the methodological level, this paper integrates three approaches to genome evolution: the duplication tree reconstruction, the gene tree/species tree reconciliation theory, and the concept of inversion median used in order-based phylogeny reconstruction. An application on a cluster of olfactory receptor genes in four mammals is presented. | 18,781,832 |
Magnetic reconstruction of three-dimensional tissues from multicellular spheroids. | Multicellular spheroids are useful building blocks for tissue reconstruction. This study reports a simple technique called magnetic organoid patterning for assembly of spheroids into a complex tissue-mimicking construct. Spheroids were labeled magnetically using co-incubation of RGD peptide-conjugated magnetic microparticles and single cells in suspension culture. The labeled spheroids can be manipulated individually or in parallel with a magnet without producing apparent effects on cell growth and migration. Spheroid patterns such as rings, lines, and arrays can be efficiently generated using this method. The patterned spheroid can be immobilized in functional hydrogels, in which fusion of neighboring spheroids and tissue-specific features were observed. Spheroid patterns temporarily encapsulated in a thermal-responsive hydrogel can be stacked layer by layer to generate thick three-dimensional (3D) tissues. These results indicate that magnetic organoid patterning is useful for construction of complex 3D tissue and will find applications in cell-to-cell interaction research, drug screening, and regenerative medicine. | 18,781,835 |
CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. | To investigate an association of responsiveness to clopidogrel loading dose with genotypes of cytochrome P450 (CYP) 2C19, other CYP isozymes and nongenetic factors in patients with coronary artery disease. Genotyping for CYP2C19 (*2, *3 and *17), CYP3A4*1B and CYP3A5*3 variants was performed in patients (n = 237) who underwent percutaneous coronary intervention. Adenosine diphosphate-induced platelet aggregation was determined after first administration of 600 mg clopidogrel. CYP2C19*2 carriers showed significantly increased residual platelet aggregation (RPA) (OR: 4.6; 95% CI: 2.5-8.7; p < 0.0001) compared with noncarriers. All other polymorphisms had no influence on RPA. For the development of a risk score for better prediction of RPA, CYP2C19*2 genotype and previously identified nongenetic risk factors (age >65 years, Type 2 diabetes mellitus, decreased left ventricular function, renal failure and acute coronary syndrome) were analyzed. Multivariable logistic regression analysis showed a significant correlation of the nongenetic factors (chi (2) = 5.32; p = 0.021) and CYP2C19*2 (chi (2) = 21.31; p < 0.0001) with high RPA, and an even higher association for the combination of both (chi (2) = 25.85; p < 0.0001). Prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors. | 18,781,853 |
Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients. | Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine--as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine--are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML. | 18,781,906 |
New methods for the identification of efflux mediated MDR bacteria, genetic assessment of regulators and efflux pump constituents, characterization of efflux systems and screening for inhibitors of efflux pumps. | We have developed a number of methods that identify efflux pump mediated multi-drug resistant bacteria, characterize efflux systems and screen for inhibitors of efflux pumps. These approaches were complemented by the quantification of the expression of genes that regulate and code for constituents of efflux pumps. The methods described are easy to use, reproducible and for the most part, require instrumentation normally present in a clinical bacteriology laboratory. Because each method provides good reproducibility, they lend themselves for inter-laboratory use. | 18,781,922 |
Biophysical characterization of in- and efflux in Gram-negative bacteria. | Gram-negative bacteria developed a number of tools to avoid accumulation of cell-toxic compounds. The outer membrane as a first defense system is tightly packed reducing permeation through the lipid membrane. Water-soluble compounds may penetrate through membrane channels called porins. Once inside the periplasmic space special enzymes may welcome the foreign molecule for inactivation. The molecules entering the inner membrane will be harvested by efflux pumps and ejected back to the extra-cellular space. Bacteria modulate all these barriers through the level of protein expression or mutations. In order to understand the function of the involved proteins a quantification of the individual transport elements is necessary. Here we describe recent biophysical methods to characterize molecular transport across membranes. | 18,781,924 |
Status of cytokines in ischemia reperfusion induced heart injury. | Extensive investigations have implicated cytokines such as tumour necrosis factor (TNF)- alpha and interleukin (IL)-1, and IL-6 as contributing to the pathology of ischemia-reperfusion (I/R) injury, since an increase in the production of those cytokines was clinically detected after myocardial infarction and cardiopulmonary bypass surgery. Current evidence indicates that these cytokines are autocrine contributors to myocardial dysfunction and cardiomyocyte necrosis in I/R injury, whereas, earlier evidence also suggest that cytokines have controversial roles in cardiovascular pathophysiology. Accordingly, it becomes vital to better define the mechanisms of action of cytokines as important steps towards the development of effective therapeutic strategies to combat their deleterious effects in ischemia-induced myocardial injury. Since TNF-alpha, TGF-beta1, IL-1, IL-6 and IL-8 have been frequently studied in cardiovascular diseases, especially in I/R heart disease, the purpose of this article is to review the cardiodepressant role of these cytokines and their release in I/R injury. | 18,781,928 |
Extra-hematopoietic effects of erythropoietin. | Erythropoietin (Epo) has a long-lasting history as the hormon that allows production of red blood cells. It is now well established that, besides erythropoiesis, Epo has the ability to sustain proliferation of myeloid lineages. More recently, extra-haematological roles have been described for Epo. Its receptor, EpoR, has been detected at the membrane of several neoplastic and normal cell types from the central nervous system and other non haematological cell lines. Whereas Epo-EpoR have been detected several years ago in some extra-haematological normal lineages, their role has long been underestimated whereas they may be crucial for proliferation and survival. Consequently, efforts have recently increased to identify the precise role of Epo-EpoR in a variety of cell types. This allowed identification of physiologically relevant targets that led to original therapeutic strategies. | 18,781,929 |
Iron involvement in multiple signaling pathways of atherosclerosis: a revisited hypothesis. | Atherosclerosis being a leading death cause in many countries is a chronic inflammatory process in which inflammation, immune activation, and oxidative stress are interactively involved. Some epidemiological and many experimental studies suggest that development of atherosclerosis is associated with the amount of iron stored in the body. Transport of electrons between different forms of iron makes it essential for many fundamental cell functions and signaling. Under pathologic conditions iron may serves as a potential catalyst, particularly in the form of redox-active iron or labile iron, for free radical reactions in oxidative stress and cell damage of atherogenesis. Emerging evidence indicates that cellular iron may participate in various cellular signaling pathways, many of which have been implicated in atherogenesis. These include iron homeostatic control signaling, iron-induced oxidative-responsive transcription factors, iron-induced activation of inflammatory cytokines, and iron-dependent signaling in cell growth and apoptosis. This review highlights research progress on atherosclerosis-relevant iron signaling and revisits our hypothesis on iron and atherosclerosis. We propose that iron may contribute to the pathogenesis of atherosclerosis not only via changes in the body iron amount but also by its regulatory roles in redox-sensitive signaling and inflammatory immune responses of atherosclerosis. | 18,781,942 |
HGF/MET signaling in ovarian cancer. | Ovarian cancer is the leading cause of death from gynecological cancers in North America and Europe. Despite its clinical significance, the factors that regulate the development and progression of ovarian cancer are among the least understood of all major human malignancies. A growth factor with pleiotropic effects, which has attracted increasing attention in recent years, is the hepatocyte growth factor (HGF) and its receptor MET. While deregulated HGF/MET signaling is observed in many tumors, the consequences of MET activation are complex and context dependent. Recent observations have demonstrated a cross-talk of other signaling pathways with MET signaling. This review summarizes the key findings and recent advances in our understanding of HGF and MET in the transformation and progression of ovarian cancer. We will begin with a brief discussion on the role of HGF and MET in the physiology of normal ovarian surface epithelium (OSE) and ovarian cancer development. In particular, the coexpression of HGF and MET in OSE of women with hereditary ovarian cancer syndromes emphasizes their importance in neoplastic transformation of OSE. The involvement of HGF in other aspects of tumor progression, such as invasion and metastasis, and novel downstream target genes activated by HGF is summarized next. The therapeutic potential of HGF to treat ovarian cancer and to improve response to conventional chemotherapy is also described. Finally, the most recent progress in drug development and future areas of research in terms of their potential clinical implications are discussed. | 18,781,954 |
Cardiovascular disease in patients with diabetic nephropathy. | Diabetic nephropathy, which represents a major form of chronic kidney disease (CKD), is a leading cause of end-stage renal disease worldwide, and is also a risk factor for cardiovascular disease (CVD). Patients with diabetes and CKD have poorer outcomes after myocardial infarction. The underlying pathogenic mechanism that links diabetic nephropathy to a high risk of CVD remains unclear. In addition to traditional risk factors, including hypertension, hyperglycemia, and dyslipidemia, identification of novel modifiable risk factors is important in preventing CVD in people with diabetes. Inflammation/oxidative stress are known to be associated with an increased risk for CVD in patients with diabetic nephropathy. Moreover, homocysteine, advanced glycation end products, asymmetric dimethylarginine, and anemia may play a role in the development and progression of atherosclerosis in patients with diabetic nephropathy. This review summarizes the epidemiologic evidence, molecular mechanisms responsible for the increased risk for CVD in patients with diabetic nephropathy, and therapeutic intervention for diabetic nephropathy as evidenced by large-scale clinical trials. | 18,781,960 |
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: novel pharmacological agents in the treatment of ischemia reperfusion injury. | Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands constitute important insulin sensitizers that have already been used for the treatment of human metabolic disorders, exerting also pleiotropic effects on inflammatory related diseases and cancer. Ischemia-reperfusion injury that is mainly associated with organ transplantation constitutes a serious complication with a great relevance in clinical practice. Accumulating experimental data have recently revealed that natural and synthetic PPAR-gamma ligands exert beneficial effects against ischemia-reperfusion injury. The present review summarizes the available information on the role of PPAR-gamma ligands in ischemia-reperfusion injury amongst the different organ systems. Taking into consideration the data so far, PPAR-gamma ligands seem to represent potential therapeutic agents in the aim to reduce or even prevent injury associated with ischemia-reperfusion. | 18,781,963 |
The many faces of amyloid beta in Alzheimer's disease. | The 'amyloid cascade hypothesis' links amyloid beta peptide (Abeta) with the pathological process of Alzheimer's disease (AD) and it still awaits universal acceptance. Amyloid precursor protein (APP), through the actions of the gamma-secretase complex, eventually becomes a different Abetaspecies. The various Abeta species have proven to be difficult to investigate under physiological conditions, and the species of Abeta responsible for neurotoxicity has yet to be unequivocally identified. The two important Abeta peptides involved are Abeta(1-40) and Abeta(1-42), and each has been ascribed both toxic and beneficial attributes. The ratio between the two species can be important in AD etiology. Additionally, shorter variants of Abeta peptides such as Abeta(1-8), Abeta(9-16) and Abeta(16) have also been shown to be potential participants in AD pathology. Interestingly, a new 56-kDa Abeta peptide (Abeta*56) disrupts memory when injected into the brains of young rats. Transgenic mice models are complicated by the interplay between various human Abeta types and the mouse Abeta types in the mouse brains. However, the accumulation of Abeta(1-42) in the brains of transgenic C. elegans worms and Drosophila is indeed detrimental. A less investigated aspect of AD is epigenetics, but in time the investigation of the role of epigenetics in AD may add to our understanding of the development of AD. | 18,781,964 |
CNS immune surveillance and neuroinflammation: endocannabinoids keep control. | To avoid inflammatory escalation, the central nervous system (CNS) harbors an impressive arsenal of cellular and molecular mechanisms enabling strict control of immune reactions. We here summarize studies suggesting that the old paradigm of the "CNS immune privilege" is overly simplistic. The immune system is allowed to keep the CNS under surveillance, but in a strictly controlled, limited and well-regulated manner. The first line of defense lies outside the brain parenchyma to spare neuronal tissue from the detrimental effects of an inflammatory immune response. As a second line of defense neuroinflammation is unavoidable when pathogens infiltrate the brain or the CNS-immune-homeostasis fails. Inflammation in the CNS is often accompanied by divers brain pathologies. We here review recent strategies to maintain brain homeostasis and modulate neuroinflammation. We focus on Multiple Sclerosis as an example of a complex neuroinflammatory disease. In the past years, several in vitro, in vivo and clinical studies suggested that the endocannabinoid system participates crucially in the immune control and protection of the CNS. We discuss here the endocannabinoid system as a key regulator mechanism of the cross talk between brain and the immune system as well as its potential as a therapeutic target. | 18,781,977 |
The endocannabinoid system in amyotrophic lateral sclerosis. | Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition characterised by the selective loss of motor neurons from the spinal cord, brainstem and motor cortex. Although the pathogenic mechanisms that underlie ALS are not yet fully understood, there is significant evidence that several neurotoxic mechanisms including excitotoxicity, inflammation and oxidative stress, all contribute to disease pathogenesis. Furthermore, recent results have established that although primarily a motor neuron specific disorder, ALS is not cell-autonomous and non-neuronal cells including astroglia and microglia play a critical role in mechanism of disease. Currently the only licensed therapy available for the treatment of ALS is the anti-glutamatergic agent Riluzole, which has limited therapeutic effects. However, there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Activation of CB(1) receptors may therefore inhibit glutamate release from presynaptic nerve terminals and reduce the postsynaptic calcium influx in response to glutamate receptor stimulation. Meanwhile, CB(2) receptors may influence inflammation, whereby receptor activation reduces microglial activation, resulting in a decrease in microglial secretion of neurotoxic mediators. Finally, cannabinoid agents may also exert anti-oxidant actions by a receptor-independent mechanism. Therefore the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS. Recent studies investigating this potential in models of ALS, in particular those that focus on strategies that activate CB(2) receptors, are discussed in this review. | 18,781,981 |
The endocannabinoid system and multiple sclerosis. | Multiple sclerosis (MS) is a neurodegenerative disease that is characterised by repeated inflammatory/demyelinating events within the central nervous system (CNS). In addition to relapsing-remitting neurological insults, leading to loss of function, patients are often left with residual, troublesome symptoms such as spasticity and pain. These greatly diminish "quality of life" and have prompted some patients to self-medicate with and perceive benefit from cannabis. Recent advances in cannabinoid biology are beginning to support these anecdotal observations, notably the demonstration that spasticity is tonically regulated by the endogenous cannabinoid system. Recent clinical trials may indeed suggest that cannabis has some potential to relieve, pain, spasms and spasticity in MS. However, because the CB(1) cannabinoid receptor mediates both the positive and adverse effects of cannabis, therapy will invariably be associated with some unwanted, psychoactive effects. In an experimental model of MS, and in MS tissue, there are local perturbations of the endocannabinoid system in lesional areas. Stimulation of endocannabinoid activity in these areas either through increase of synthesis or inhibition of endocannabinoid degradation offers the positive therapeutic potential of the cannabinoid system whilst limiting adverse events by locally targeting the lesion. In addition, CB(1) and CB(2) cannabinoid receptor stimulation may also have anti-inflammatory and neuroprotective potential as the endocannabinoid system controls the level of neurodegeneration that occurs as a result of the inflammatory insults. Therefore cannabinoids may not only offer symptom control but may also slow the neurodegenerative disease progression that ultimately leads to the accumulation of disability. | 18,781,983 |
Brain tumour stem cells: implications for cancer therapy and regenerative medicine. | The cancer relapse and mortality rate suggest that current therapies do not eradicate all malignant cells. Currently, it is accepted that tumorigenesis and organogenesis are similar in many respects, as for example, homeostasis is governed by a distinct sub-population of stem cells in both situations. There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells (CSC), which are characterized by their self-renewing capacity and differentiation ability. The investigation of solid tumour stem cells has gained momentum particularly in the area of brain tumours. Gliomas are the most common type of primary brain tumours. Nearly two-thirds of gliomas are highly malignant lesions with fast progression and unfortunate prognosis. Despite recent advances, two-year survival for glioblastoma (GBM) with optimal therapy is less than 30%. Even among patients with low-grade gliomas that confer a relatively good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and a tumour-initiating function. In general, this fraction is characterized for forming neurospheres, being endowed with drug resistance properties and often, we can isolate some of them using sorting methods with specific antibodies. The molecular characterization of these stem populations will be critical to developing an effective therapy for these tumours with very dismal prognosis. To achieve this aim, the development of a mouse model which recapitulates the nature of these tumours is essential. This review will focus on glioma stem cell knowledge and discuss future implications in brain cancer therapy and regenerative medicine. | 18,782,002 |
Trends in metabolic syndrome and gene networks in human and rodent models. | Metabolic syndrome (MetS) can be considered a pheno-physiological cluster of metabolically interrelated risk factors for diabetes mellitus and cardiovascular disease. MetS has emerged as a result of complex interactions among environmental stresses and MetS gene networks and their products. In this review we summarize trends in MetS definitions, their associated controversies and possibilities for their refinement. The National Cholesterol Education Program MetS definition with its improvements by the American Heart Association and NHLBI Conference has the potential to become the primary clinical definition of MetS. For the first time, by reviewing a large body of literature, we construct MetS gene networks in humans and in rodents. These MetS gene networks can serve as a budding platform to develop new hypotheses regarding the genetic mechanisms underlying MetS. We also extend the notion of MetS to mouse models. New and improved molecular genomics and proteomic tools have been developed in parallel with the MetS epidemic which in conjunction with improved and novel computational statistical methods have magnified the genetic resolution of MetS analyses. Our results justify the existence of MetS as a meaningful syndrome and suggest that a better understanding of its etiology can benefit the health of human kind. | 18,782,016 |
Potassium channel openers and improvement of toxic stress: do they have role in the management of inflammatory bowel disease? | Inflammatory bowel disease (IBD) is a progressive condition in gastrointestinal tract, which refers to two idiopathic diseases; ulcerative colitis and Crohn's disease. Although certain etiology of these conditions is not known, it seems that an abnormality in reaction and regulation of the immune system plays an important role in adventure of the disease. According to the investigations, it is likely that oxidative and nitrosative stress have etiologic roles in IBD. Their destructive effects may contribute to the initiation or progression of the disease. Nowadays, the effectiveness of different medicines in the treatment of IBD has been proved, but none of them has shown a desirable result. Potassium channel openers (PCOs) are a class of drugs with various usages in the aspects of cardiovascular diseases and urinary incontinence. Their major mechanism is the opening of ATP-sensitive potassium (K-ATP) channels and contribute to the relaxation of smooth muscles. Nicorandil is a member of PCOs, with a special chemical structure. Recent investigations mention some novel effects and functions for this drug. Nicorandil reveals an anti-apoptosis property not only via a nitric oxide (NO)/cGMP-dependent mechanism, but also through activating mitochondrial K-ATP channels. Nicorandil can also elevate cGMP levels in some tissues, without direct NO generation. Gastroprotective activity via opening of the K channels, free radical scavenging, prostaglandin E2 elevation, decreasing pepsin and acid secretion, and prevention of the detrimental rise in NO has been proposed for nicorandil. According to these protective mechanisms and the role of oxidative/nitrosative stress in the expression of IBD, we herein hypothesize that nicorandil and other PCOs with similar structure can be used in the management of IBD. This approach offers new hope for the successful treatment of IBD. Further investigations on animal models are needed, to place nicorandil and similar drugs alongside IBD therapy. | 18,782,019 |
Synthesis and antimalarial activity of new amino analogues of amodiaquine. | Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development. | 18,782,038 |
N,N-Bis(trifluoromethylquinolin-4-yl)diamino alkanes: synthesis and antimalarial activity. | A series of N,N-bis(trifluoromethylquinolin-4-yl)- and N,N-bis[2,8-bis(trifluoromethyl)quinolin-4-yl] diamino alkane and piperazine derivatives were synthesised by employing a simple and rapid displacement reaction of the 4-chloro group on the 2-trifluoromethyl- and 2,8-bis(trifluoromethyl)-quinoline by diaminoalkane or piperazine groups. Results of in vitro antimalarial activity evaluations of these compounds against the chloroquine-sensitive (D10) and chloroquine-resistant (K1) strains of Plasmodium falciparum indicate that compounds with trifluoromethyl groups in both the 2 and 8 positions coupled with diaminoalkyl bridging chains of 2 to 6 carbon atoms exhibit a slightly higher activity than compound with only a trifluoromethyl group at position 2, and those with a piperazine bridge. These compounds exhibit higher activity in the chloroquine-resistant than in the chloroquine-sensitive strains of the Plasmodium. Comparative studies indicate that the compounds are more selective in their cytotoxicity against the parasite cells. Except for compounds containing a piperazine bridge, this new series of compounds interact with ferriprotoporphyrin IX to more or less the same extent. | 18,782,040 |
Dibenzoylmethane activates Nrf2-dependent detoxification pathway and inhibits benzo(a)pyrene induced DNA adducts in lungs. | Cigarette smoke derived carcinogens have been identified as the main agents implicated in lung carcinogenesis. Epidemiological as well as animal studies have indicated that certain phytochemicals can block the carcinogenic process by enhancing the detoxification of environmental and or dietary carcinogens. Dibenzoylmethane (DBM), a minor constituent of licorice, is a beta-ketone analog of curcumin, a promising chemopreventive agent for colon, breast and skin cancer. The present study was designed to examine the chemopreventive efficacy of DBM in lungs, its global molecular targets and the mechanism of its action. Feeding DBM to A/J mice significantly inhibited benzo[a]pyrene induced DNA adducts in lungs. Further analysis of its global molecular targets in lungs by oligonucleotide microarray revealed expression of several cytoprotective genes including phase II enzymes that are regulated by Nrf2, a basic leucine zipper transcription factor. To decipher if DBM mediates its function via Nrf2 activation, Nrf2 dependent reporter assays were performed. DBM elicited a dose-dependent increase in antioxidant response element (ARE)-driven luciferase reporter activity which correlated with an increase in mRNA expression of NQO1, GSTA2, and GCLC in mouse hepatoma cells, which are well established targets of Nrf2. Conversely, DBM stimulated ARE reporter activity was attenuated by a dominant-negative mutant of Nrf2. Electrophoretic mobility shift assay confirmed that DBM greatly increased the DNA binding activity of Nrf2. In conclusion, DBM mediates the induction of phase II enzymes by Nrf2 activation and inhibits benzo[a]pyrene induced DNA adducts by enhancing its detoxification in lungs. | 18,782,044 |
Synthesis and biological evaluation of naphthalene-1,4-dione derivatives as potent antimycobacterial agents. | The recent increase in the incidence of tuberculosis with the emergence of multi-drug resistant (MDR) cases has lead to the search for new drugs that are effective against MDR strains of Mycobacterium tuberculosis (M. tb) and can augment the potential of existing drugs against tuberculosis. In the present study a series of naphthalene-1,4-dione derivatives were synthesized and evaluated for their in vitro antimycobacterial activity against M. tb H37Rv strain. Preliminary results indicated that most of the compounds demonstrated significant antimycobacterial activities. The most effective compounds of the series 7, 8 and 10 have MIC values of 3.13 microg/mL and growth inhibition of 99%. Compound 7 has an IC50 value of 0.49 microg/mL. Compounds 1, 3 and 18 with MIC values of 3.13 microg/mL also showed 96-98% growth inhibition. The objective of our study is to generate new leads through different mode of action and to optimize their structure to display the potent efficacy. | 18,782,046 |
Crystal structure of SCO6571 from Streptomyces coelicolor A3(2). | SCO6571 protein from Streptomyces coelicolor A3(2) was overexpressed and purified using Rhodococcus erythropolis as an expressing host. Crystals of selenomethionine-substituted SCO6571 have been obtained by vapor diffusion method. SCO6571 crystals diffract to 2.3 A and were found to belong to the orthorhombic space group P2(1)2(1)2(1) with unit cell parameters a = 84.5, b = 171.6, c = 184.8 A. Six molecules in the asymmetric unit give a crystal volume per protein mass (V(M)) of 2.97 A (3) Da(-1) and solvent content of 58.6 %. The structure was solved by the single wavelength anomalous diffraction (SAD) method. SCO6571 is a TIM-barrel fold protein that assembles into a hexameric molecule with D(3) symmetry. | 18,782,066 |
Chemotherapy in addition to preoperative radiotherapy in locally advanced rectal cancer - a systematic overview. | The value of chemotherapy with radiotherapy has been explored in recent randomised clinical trials in locally advanced rectal cancer (LARC). An overview of these trials was made together with a discussion of what constitutes LARC. Although imaging is required for adequate staging of primary rectal cancer, the term 'locally' advanced has no consistent definition and has been used differently in the trials. Three large randomised trials, however, in different subsets, show that radiochemotherapy (RTCT) with 5-FU-based treatment compared to the same radiotherapy (RT) improves local control and has some influence on systemic relapses and possibly overall survival, without being too toxic. Whether the chemotherapy acts as a radiosensitizer is not known. Preoperative short-course RT alone (5 x 5 Gy) had in one trial similar activity as preoperative RTCT and less toxicity and was, in another trial, superior to selectively given postoperative RTCT. In conclusion, preoperative RTCT, using 5-FU is a new evidence-based treatment in the most locally advanced rectal cancers (T4 tumours growing into neighbouring organs), whereas its use in the slightly less advanced cancers could be discussed. Several phase I - II trials have indicated that combinations of drugs with RT can be even more efficient, but this must be proven in randomised trials since patient selection is of great importance. | 18,782,078 |
The role of cetuximab and other epidermal growth factor receptor monoclonal antibodies in the treatment of advanced non-small cell lung cancer. | Lung cancer continues to be the leading cause of cancer-related deaths in the western civilization and developing countries. Non-small cell lung cancer (NSCLC) accounts for > 85% of all cases of lung cancer. Since most patients with NSCLC have advanced disease at diagnosis, to date chemotherapy with third-generation platinum-based doublets represents the standard of care. However, a plateau has been reached with the use of cytotoxic chemotherapy in advanced NSCLC. Advances in the knowledge of tumour biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. In particular, the epidermal growth factor receptor (EGFR), a member of the ErbB family and commonly overexpressed in NSCLC, is one of the most studied targets. Overexpression of EGFR has been associated with a poorer prognosis in patients with cancer, therefore its inhibition may lead to the suppression of tumor proliferation improving clinical outcome. Strategies to block EGFR include development of monoclonal antibodies to EGFR, tyrosine kinase inhibitors, ligand-linked toxins, and antisense approaches. This article will focus on cetuximab and other monoclonal antibodies and their applications in the treatment of advanced NSCLC. | 18,782,080 |
Mediterranean diet is associated with reduced asthma and rhinitis in Mexican children. | Diet during pregnancy and childhood has been suggested to play an important role in children's asthma risk. We assessed whether the adherence to a Mediterranean dietary pattern, for children in the last 12 months and their mothers during pregnancy, was associated with both childhood asthma and allergic rhinitis. A cross-sectional study was conducted in 2004 using a random sample of 1476 children (6- to 7-year old) from the Mexicali region, Mexico. Dietary data of children's intake in the last 12 months and their mothers' intake during pregnancy was collected, through a parental food frequency questionnaire. A Mediterranean diet score was computed [Trichopoulou et al., N Engl J Med 348 (2003), 2599]. Data on seven asthma and rhinitis-related outcomes were obtained from the International Study of Asthma and Allergies in Childhood questionnaire. Adherence to a Mediterranean dietary pattern was inversely associated with asthma ever (OR = 0.60, 95% CI = 0.40-0.91), wheezing ever (0.64, 0.47-0.87), rhinitis ever (0.41, 0.22-0.77), sneezing ever (0.79, 0.59-1.07), current sneezing (0.71, 0.52-0.96) and current itchy-watery eyes (0.63, 0.42-0.95). No associations were found using the mothers' pregnancy diet score, except for current sneezing (0.71, 0.53-0.97). Our findings suggest a protective effect of following a healthy dietary pattern on asthma and allergic rhinitis in Mexican children. | 18,782,109 |
Alterations of the ocular surface epithelial MUC16 and goblet cell MUC5AC in patients with atopic keratoconjunctivitis. | An increased understanding of the ocular surface at cellular level in the conjunctiva and the cornea may help explain the pathogenesis and the subsequent clinical appearance of atopic ocular allergies, which may be potentially blinding. To investigate the MUC16 and MUC5AC alterations, tear function and the ocular surface disorder in patients with atopic keratoconjunctivitis (AKC). Thirty-six eyes of 18 AKC patients as well as 28 eyes of 14 age- and sex-matched normal subjects were studied. The subjects underwent corneal sensitivity measurements, Schirmer test, tear film break-up time (BUT), fluorescein and Rose-Bengal staining of the ocular surface, conjunctival impression cytology and brush cytology. Impression cytology samples underwent periodic acid schiff and immunohistochemical staining with MUC16 and MUC5AC antibodies. Brush cytology specimens underwent evaluation for inflammatory cell numbers and quantitative real-time polymerase chain reaction (PCR) for MUC16 and MUC5AC mRNA expression. The mean corneal sensitivity and BUT values were significantly lower in patients with AKC, compared with controls (P < 0.001). Brush cytology specimens from AKC patients revealed significantly higher numbers of inflammatory cells (P < 0.001). Specimens from patient eyes showed positive staining for MUC5AC and MUC16. MUC16 mRNA expression was significantly upregulated with significant downregulation of MUC5AC mRNA expression in eyes with AKC compared with the eyes of control subjects. Ocular surface inflammation, decline in corneal sensitivity, tear film instability, changes in conjunctival epithelial MUC5AC and MUC16 mRNA expressions were thought to be important in the pathogenesis of atopic ocular surface disease. | 18,782,111 |
Histamine H4 receptors modulate dendritic cell migration through skin--immunomodulatory role of histamine. | Dendritic cells (DC) are the major antigen-presenting cells and play a key role in adaptive immunity as they are able to activate naive T cells. It was recently described, that the histamine H(4) receptor (H4R) is present on human monocyte-derived DC and that chemotaxis and T-helper (Th)1-Th2 polarization is mediated by this receptor. However, the distribution of histamine receptors on murine DC has not been studied yet. The histamine receptor expression on murine bone marrow (BM)-derived DC and effects of histamine and H4R agonism on DC migration through skin were studied. As it was demonstrated in scratching experiments that NMRI mice are more susceptible to H4R-mediated itch than BALB/c mice, DC function of NMRI and BALB/c mice was compared. The mRNA of the H1R, H2R and H4R could be detected in murine BM-derived DC, while mRNA of the H3R was found to be low or undetectable. There were no distinct differences in mRNA expression and in H4R protein level (flow cytometry) between NMRI compared with BALB/c mice indicating, that a higher susceptibility is not associated with a generally higher H4R expression in all cell types. Histamine as well as the H4R agonist clobenpropit induced an enhanced chemotaxis in the skin DC migration assay. The enhanced chemotaxis was blocked by the H4R antagonist JNJ7777120. This finding was confirmed by in vitro migration experiments with BM-derived DC. Referring to DC migration, blocking the H4R on inflammatory cells might be a promising anti-inflammatory, immunomodulatory strategy. | 18,782,117 |
Clinical practice of functional electrical stimulation: from "Yesterday" to "Today". | Functional electrical stimulation (FES) is an accepted treatment method for paresis or paralysis after spinal cord and head injury as well as stroke and other neurological upper motor neuron disorders. At the beginning, FES worked like an electrophysiological brace for the correction of drop foot of patients after a stroke. When analyzing early accomplishments, it becomes evident that FES was influenced rather by technological and biomedical engineering development than by contemporary knowledge on neurocontrol of movement in individuals with upper motor neuron paralysis. Nevertheless, with better understanding of pathophysiology of spasticity and neurocontrol of impaired movement, FES advanced from an electrophysiological brace to a treatment modality for the improvement of muscle control, neuroaugmentation of residual movements, and supportive procedure for "spontaneous recovery" of motor control. In the present article we shall illustrate barriers which delayed FES to be applied in clinical practice of neuron rehabilitation from "Yesterday" to "Today." We shall discuss the importance to apply FES early after the onset of neurological conditions to prevent disuse of noninjured portions of the CNS. Moreover, FES can play a significant role in the supporting processes of neuroplasticity in the subacute phase of upper motor neuron dysfunction. Therefore, the electrophysiological brace of "Yesterday" provides "Today" a correction of missing neuromuscular function. At the same time, it is an active external device for the correction of motor deficits interacting with the somatosensory-motor integration. Thus, "Yesterday" and "Today" of the same technological approach can be very different, thanks to a different understanding and assessment of "external" and "internal" components of human motor control. | 18,782,124 |
Searching for realism, structure and agency in Actor Network Theory. | Superficially, Actor Network Theory (ANT) and critical realism (CR) are radically opposed research traditions. Written from a realist perspective, this paper asks whether there might be a basis for finding common ground between these two traditions. It looks in turn at the questions of realism, structure, and agency, analysing the differences between the two perspectives and seeking to identify what each might learn from the other. Overall, the paper argues that there is a great deal that realists can learn from actor network theory; yet ANT remains stunted by its lack of a depth ontology. It fails to recognize the significance of mechanisms, and of their dependence on emergence, and thus lacks both dimensions of the depth that is characteristic of critical realism's ontology. This prevents ANT from recognizing the role and powers of social structure; but on the other hand, realists would do well to heed ANT's call for us to trace the connections through which structures are constantly made and remade. A lack of ontological depth also underpins ANT's practice of treating human and non-human actors symmetrically, yet this remains a valuable provocation to sociologists who neglect non-human entities entirely. | 18,782,150 |
Reconceptualizing reflexivity and dissonance in professional and personal domains. | Debates around 'reflexivity' and the construction of the gendered self within late modernity have occupied the attention of both 'reflexive modernization' theorists (Beck, Giddens and Lash 1994; Beck and Beck-Gernsheim 1996; Giddens 1991, 1992) as well as gender and feminist theorists. While theorists such as Beck and Giddens have been preoccupied with establishing the connection between reflexivity and the construction of the 'non-gendered' self, gender and feminist theorists have sought to amplify the debate by exploring the intersecting nexus of contemporary theorizing, more fully within this context. This paper explores the theoretical underpinnings of these debates and their application to specific professional and personal domains. I consider three case studies to assess these issues as outlined in my own work, Brooks 2006, and in the work of Wajcman and Martin 2002, and McDowell 1997, which draw on empirical research and explore changes to gender identity within professional and personal domains. I conclude that there is little evidence in the research presented here of any systematic reconfiguring of gender identities leading to a detraditionalization of gender as suggested by the 'reflexive modernization' theorists. | 18,782,154 |
Dental utilization for Medicaid-enrolled adults with developmental disabilities in Iowa residential care facilities. | The goal of this study was to evaluate the dental utilization of Medicaid-enrolled adults in Iowa residential care facilities (n=1423). Medicaid enrollment and claims files for 2003 were used, as well as information from the Iowa Department of Inspections and Appeals. Dental utilization was defined as having any dental visit during 2003. Of the residents, 74.1% utilized at least one dental service in 2003. Residents in facilities that were part of smaller organizations, and younger residents, were more likely to have had a dental visit. Of those with a visit, over 80% received a preventive service but this declined with age. Despite additional barriers, dental utilization was generally good for Medicaid-enrolled residents of residential care facilities in Iowa. Residents in smaller facilities of smaller organizations received more personalized care. Older residents were less likely to have a parent involved, were more likely to be edentulous, and sought care less frequently. | 18,782,194 |
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