Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry.
Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10-8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors.See related commentary by Brown and Richard, p. 2272.


Nanodisc reconstitution of flavin mononucleotide binding domain of cytochrome-P450-reductase enables high-resolution NMR probing.
Cytochrome-P450-reductase transfers electrons to cytochrome-P450 through its flavin mononucleotide binding domain (FBD). Despite the importance of membrane-anchoring for FBD function, studies have focused on its soluble domain lacking the transmembrane-domain. Here we demonstrate that the reconstitution of FBD in nanodiscs enables high-resolution NMR measurements and renders a stable conformation.


Issues in adherence with pediatric regimens.
Adherence to recommendations for health care is an area of serious concern for pediatric psychologists. The present article highlights several key issues affecting research and clinical work in this area. They include: difficulties defining and measuring adherence; developmental aspects of adherence; special concerns with low income populations; and limitations of intervention research. In addition, several directions for future investigation in the area of pediatric adherence are addressed.


Model for the exceptional reactivity of peroxiredoxins 2 and 3 with hydrogen peroxide: a kinetic and computational study.
Peroxiredoxins (Prx) are thiol peroxidases that exhibit exceptionally high reactivity toward peroxides, but the chemical basis for this is not well understood. We present strong experimental evidence that two highly conserved arginine residues play a vital role in this activity of human Prx2 and Prx3. Point mutation of either ArgI or ArgII (in Prx3 Arg-123 and Arg-146, which are ∼3-4 Å or ∼6-7 Å away from the active site peroxidative cysteine (C(p)), respectively) in each case resulted in a 5 orders of magnitude loss in reactivity. A further 2 orders of magnitude decrease in the second-order rate constant was observed for the double arginine mutants of both isoforms, suggesting a cooperative function for these residues. Detailed ab initio theoretical calculations carried out with the high level G4 procedure suggest strong catalytic effects of H-bond-donating functional groups to the C(p) sulfur and the reactive and leaving oxygens of the peroxide in a cooperative manner. Using a guanidinium cation in the calculations to mimic the functional group of arginine, we were able to locate two transition structures that indicate rate enhancements consistent with our experimentally observed rate constants. Our results provide strong evidence for a vital role of ArgI in activating the peroxide that also involves H-bonding to ArgII. This mechanism could explain the exceptional reactivity of peroxiredoxins toward H(2)O(2) and may have wider implications for protein thiol reactivity toward peroxides.


Nanotechnology solutions to restore antibiotic activity.
This review focuses on the development of nanoparticle systems that enables to enhance and restore the antibiotic activity for drug-resistant organisms. New and more aggressive antibiotic resistant bacteria and parasites calls for the development of new therapeutic strategies to overcome the inefficiency of conventional antibiotics and bypass treatment limitations related to these pathologies. Nanostructured biomaterials, nanoparticles in particular, have unique physicochemical properties such as ultra-small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby overcoming some of the limitations in traditional antimicrobial therapeutics. Here the current progress and challenges in synthesizing nanoparticle platforms for restoring activity of various antimicrobial drugs are reviewed with an emphasis on antibiotics. We also call attention to the need to unite the shared interest between nanoengineers and microbiologists in developing nanotechnology for the treatment of microbial diseases.


Debug Your Bugs - How NLRs Shape Intestinal Host-Microbe Interactions.
The host's ability to discriminate friend and foe and to establish a precise homeostasis with its associated microbiota is crucial for its survival and fitness. Among the mediators of intestinal host-microbe interactions, NOD-like receptor (NLR) proteins take center stage. They are present in the epithelial lining and innate immune cells that constantly monitor microbial activities at the intestinal barrier. Dysfunctional NLRs predispose to intestinal inflammation as well as sensitization to extra-intestinal immune-mediated diseases and are linked to the alteration of microbial communities. Here, we review advances in our understanding of their reciprocal relationship in the regulation of intestinal homeostasis and implications for intestinal health.


Glycemic variability in inadequately controlled type 1 diabetes and type 2 diabetes on intensive insulin therapy: a cross-sectional, observational study.
Glycemic variability is suggested to be a predictor for the risk of complications of diabetes. A multitude of parameters to express glycemic variability have been described, but no gold standard exists. The easy measurable parameter SD has been shown to be strongly related to other parameters in a group of patients with mostly well-controlled type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Glycemic variability is higher in T1DM compared with T2DM in mixed populations with different treatments, but studies in patients on intensive insulin treatment are lacking. Therefore in this study we investigate different parameters of glycemic variability and differences between T1DM and T2DM in inadequately controlled patients on intensive insulin treatment. In this cross-sectional, observational study we describe glycemic variability, measured as SD, coefficient of variation, continuous overall net glycemic action, and mean of daily differences in a cohort of inadequately controlled T1DM (n = 166) and T2DM (n = 58) patients on intensive insulin treatment. SD of 48 h (SD(total)) was highly correlated to all other measured parameters of glycemic variability (r = 0.66-0.88). All parameters of glycemic variability were significantly higher in T1DM compared to T2DM (P < 0.001), although hemoglobin A1c and mean glucose were comparable and treatment regimen was the same. In the cohort of T2DM patients but not T1DM, a longer duration of insulin therapy was associated with higher glycemic variability. SD(total) is a conveniently measurable parameter to express glycemic variability in patients with inadequate control with intensive insulin therapy. Patients with T1DM and long-lasting T2DM have the highest glycemic variability.


Invasive nontyphoidal Salmonella disease: epidemiology, pathogenesis and diagnosis.
This review highlights and discusses important publications over the past 12 months providing new insights on invasive nontyphoidal Salmonella (iNTS) disease. There have been informative new estimates of the burden of iNTS in Asia and in high-resource, low-incidence settings. Important information has emerged in the last year about the relationships between HIV, malaria, iNTS and typhoid fever in adults and children in Africa. HIV causes susceptibility to iNTS disease, but has been shown to be protective against typhoid fever. Clinical guidelines for presumptive diagnosis frequently fail to identify iNTS disease in Africa, and there remains a need for improved diagnostic tools. Experimental studies in humans have helped us to understand the intracellular pathogenesis of iNTS and to direct the search for appropriate protein vaccine targets. The most important remaining gap in our knowledge is probably an understanding of how NTS is transmitted, and the nature of the relationship between diarrhoeal disease, carriage and invasive disease in Africa, so that diagnostic and prevention tools can be appropriately directed.


Perceptual illusion and the real-time control of action.
Participants were cued by an auditory tone to grasp a target object from within a size-contrast display. The peak grip aperture was unaffected by the perceptual size illusion when the target array was visible between the response cue and movement onset (vision trials). The grasp was sensitive to the illusion, however, when the target array was occluded from view when the response was cued (occlusion trials). This was true when the occlusion occurred 2.5 s before the response cue (delay), but also when the occlusion coincided with the response cue (no-delay). Unlike previous experiments, vision and occlusion trials were presented in random sequence. The results suggest that dedicated, real-time visuomotor mechanisms are engaged for the control of action only after the response is cued, and only if the target is visible. These visuomotor mechanisms compute the absolute metrics of the target object and therefore resist size-contrast illusions. In other situations (e.g. prior to the response cue, or if the target is no longer visible), a perceptual representation of the target object can be used for action planning. Unlike the real-time visuomotor mechanisms, perception-based movement planning makes use of relational metrics, and is therefore sensitive to size-contrast illusions.


Quantitative measurement of intracellular HDAC1/2 drug occupancy using a trans-cyclooctene largazole thiol probe.
Histone deacetylases (HDACs) regulate diverse cellular processes, and are promising targets for a number of diseases. Here we describe the design and utilization of a largazole-based chemical probe to quantitatively measure the intracellular occupancy of HDAC1 and HDAC2 by dacinostat. Surprisingly, the probe was unable to enrich HDAC3 despite its nanomolar potency in a biochemical assay, further proving the necessity of cell-based target occupancy assays to understand compound potency in physiologically-relevant settings. This occupancy assay has the potential to aid the development of novel HDAC1/2 inhibitors in drug discovery.


Comparison of ocular response analyzer parameters in chinese subjects with primary angle-closure and primary open-angle glaucoma.
To evaluate corneal hysteresis (CH) and intraocular pressure (IOP) measured by the Ocular Response Analyzer in Chinese subjects with primary angle-closure glaucoma (PACG), assess their relationship with Goldmann applanation tonometry (GAT) measurements, and compare this with subjects with primary open-angle glaucoma (POAG) and normal controls. In this prospective observational study, consecutive subjects with PACG and POAG without prior intraocular surgery were enrolled from glaucoma clinics. Normal subjects were recruited from an ongoing population-based study. One eye of each subject underwent standardized ocular examination and IOP measurement by GAT and the Ocular Response Analyzer. Corneal hysteresis and corneal-compensated IOP were compared between groups. Of the 443 subjects recruited, 131 had PACG, 162 had POAG, and 150 were normal. Corneal hysteresis was lower in PACG (9.1 mm Hg; 95% confidence interval [CI], 8.7 to 9.4 mm Hg) and POAG (9.5 mm Hg; 95% CI, 9.2 to 9.5 mm Hg) eyes compared with control eyes (10.4 mm Hg; 95% CI, 10.1 to 10.6 mm Hg; P < .001 for both), with no difference (P = .16) in CH found between PACG and POAG eyes. After adjusting for age, sex, and IOP measurement by GAT, CH persisted to be lower only in eyes with PACG in comparison with control eyes (9.4 vs 10.1 mm Hg; P = .006). Eyes with POAG had lower CH than control eyes but the difference was not statistically significant (9.6 vs 10.1 mm Hg; P = .06). Corneal hysteresis was lower in eyes with glaucoma. After adjusting for age, sex, and IOP measurement by GAT, a persistently lower hysteresis was noted in eyes with PACG compared with other groups.


Use of Multiple Fluid Biomarkers for Predicting the Co-occurrence of Diabetes and Hypertension Using Machine Learning Approaches.
The co-existence of diabetes and hypertension can complicate and affect the management of these diseases. The early detection of these comorbidities can help in developing personalized preventive treatments and thereby, reduce the healthcare burden. The inclusion of readily available fluid biomarkers from different body fluids can be used as diagnostic tools and can facilitate in the designing of treatment strategies. In this work, an attempt has been made using multiple fluid biomarkers to differentiate diabetic from diabetic and hypertensive comorbid (DHC) condition. The fluid biomarkers are obtained from a publicly available dataset for diabetic (N=105) and DHC (N=57) conditions. The features, such as systolic blood pressure, fasting blood glucose, diastolic blood pressure, and total cholesterol are extracted and statistically analyzed. Data balancing technique namely synthetic minority oversampling technique is applied on the minority class to balance the dataset. Machine learning techniques namely, linear discriminant analysis, random forest, K-nearest neighbor, and linear support vector machine are used to perform the classification between the two groups. The results show that systolic blood pressure, diastolic blood pressure, and total cholesterol are elevated in the comorbid condition. These features also exhibit a statistical significance (p<0.001) between the two groups. This study also addresses the data imbalance issue, which is resolved by using an oversampling technique to mitigate the bias resulting from imbalanced data. The LDA classifier achieves a maximum accuracy of 61.2% in distinguishing between the two conditions. Machine learning based approaches may help in the prediction of comorbid conditions. This can act as a guideline for future studies on the progression of diseases and the identification of fluid biomarkers.


The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing.
The faithful replication of genomic DNA is crucial for maintaining genome stability. In eukaryotes, DNA rereplication is prevented by the temporal regulation of replication licensing. Replication-licensing factors are required to form prereplicative complexes during G1 phase, but are inactivated in S phase to prevent rereplication. A vertebrate CUL4 CRL ubiquitin ligase (CRL4) complex containing Cdt2 as the substrate recognition subunit promotes proper DNA replication, in part, by degrading the replication-licensing factor Cdt1 during S phase. We show that the Caenorhabditis elegans CRL4(Cdt2) complex has a conserved role in degrading Cdt1. Furthermore, we show that CRL4(Cdt2) restrains replication licensing in both C. elegans and humans by targeting the degradation of the cyclin-dependent kinase (CDK) inhibitors CKI-1 and p21(Cip1), respectively. Human CRL4(Cdt2) targets the degradation of p21 in S phase, with the in vivo ubiquitylation of p21 by CRL4(Cdt2) dependent on p21 binding to PCNA. Inactivation of Cdt2 induces rereplication, which requires the presence of the CDK inhibitor p21. Strikingly, coinactivation of CRL4(Cdt2) and SCF(Skp2) (which redundantly targets p21 degradation) prevents the nuclear export of the replication-licensing factor Cdc6 during S phase, and the block on nuclear export is dependent on p21. Our work defines the degradation of p21 as a critical aspect of replication licensing in human cells.


Plastidial localization of a potato 'Nudix' hydrolase of ADP-glucose linked to starch biosynthesis.
Escherichia coli and potato (Solanum tuberosum) ADP-sugar pyrophosphatases (EcASPP and StASPP, respectively) are 'Nudix' hydrolases of the bacterial glycogen and starch precursor molecule, ADP-glucose (ADPG). We have previously shown that potato leaves expressing EcASPP either in the cytosol or in the chloroplast exhibited large reductions in the levels of starch, suggesting the occurrence of cytosolic and plastidial pools of ADPG linked to starch biosynthesis. In this work, we produced and characterized potato and Arabidopsis plants expressing EcASPP and StASPP fused with green fluorescent protein (GFP). Confocal fluorescence microscopy analyses of these plants confirmed that EcASPP-GFP has a cytosolic localization, whereas StASPP-GFP occurs in the plastid stroma. Both source leaves and potato tubers from EcASPP-GFP-expressing plants showed a large reduction of the levels of both ADPG and starch. In contrast, StASPP-GFP-expressing leaves and tubers exhibited reduced starch and normal ADPG contents when compared with control plants. With the exception of starch synthase in StASPP-GFP-expressing plants, no pleiotropic changes in maximum catalytic activities of enzymes closely linked to starch metabolism could be detected in EcASPP-GFP- and StASPP-GFP-expressing plants. The overall data (i) show that potato plants possess a plastidial ASPP that has access to ADPG linked to starch biosynthesis and (ii) are consistent with the occurrence of plastidic and cytosolic pools of ADPG linked to starch biosynthesis.


Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth.
MicroRNAs (miRNAs) play important roles in cancer development. By cloning and sequencing of a HPV16(+) CaSki cell small RNA library, we isolated 174 miRNAs (including the novel miR-193c) which could be grouped into 46 different miRNA species, with miR-21, miR-24, miR-27a, and miR-205 being most abundant. We chose for further study 10 miRNAs according to their cloning frequency and associated their levels in 10 cervical cancer- or cervical intraepithelial neoplasia-derived cell lines. No correlation was observed between their expression with the presence or absence of an integrated or episomal HPV genome. All cell lines examined contained no detectable miR-143 and miR-145. HPV-infected cell lines expressed a different set of miRNAs when grown in organotypic raft cultured as compared to monolayer cell culture, including expression of miR-143 and miR-145. This suggests a correlation between miRNA expression and tissue differentiation. Using miRNA array analyses for age-matched normal cervix and cervical cancer tissues, in combination with northern blot verification, we identified significantly deregulated miRNAs in cervical cancer tissues, with miR-126, miR-143, and miR-145 downregulation and miR-15b, miR-16, miR-146a, and miR-155 upregulation. Functional studies showed that both miR-143 and miR-145 are suppressive to cell growth. When introduced into cell lines, miR-146a was found to promote cell proliferation. Collectively, our data indicate that downregulation of miR-143 and miR-145 and upregulation of miR-146a play a role in cervical carcinogenesis.


Cystatin C: efficacy as screening test for reduced glomerular filtration rate.
Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.


A small cohort of Island Southeast Asian women founded Madagascar.
The settlement of Madagascar is one of the most unusual, and least understood, episodes in human prehistory. Madagascar was one of the last landmasses to be reached by people, and despite the island's location just off the east coast of Africa, evidence from genetics, language and culture all attests that it was settled jointly by Africans, and more surprisingly, Indonesians. Nevertheless, extremely little is known about the settlement process itself. Here, we report broad geographical screening of Malagasy and Indonesian genetic variation, from which we infer a statistically robust coalescent model of the island's initial settlement. Maximum-likelihood estimates favour a scenario in which Madagascar was settled approximately 1200 years ago by a very small group of women (approx. 30), most of Indonesian descent (approx. 93%). This highly restricted founding population raises the possibility that Madagascar was settled not as a large-scale planned colonization event from Indonesia, but rather through a small, perhaps even unintended, transoceanic crossing.


Haploinsufficiency of the murine polycomb gene Suz12 results in diverse malformations of the brain and neural tube.
Polycomb proteins are epigenetic regulators of gene expression. Human central nervous system (CNS) malformations are congenital defects of the brain and spinal cord. One example of a human CNS malformation is Chiari malformation (CM), which presents as abnormal brainstem growth and cerebellar herniation, sometimes accompanied by spina bifida and cortical defects; it can occur in families. Clinically, CM ranges from an asymptomatic condition to one with incapacitating or lethal symptoms, including neural tube defects and hydrocephalus. However, no genes that are causally involved in any manifestation of CM or similar malformations have been identified. Here, we show that a pathway that involves Zac1 (also known as Plagl1 or Lot1) and controls neuronal proliferation is altered in mice that are heterozygous for the polycomb gene Suz12, resulting in a phenotype that overlaps with some clinical manifestations of the CM spectrum. Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem, accompanied by occipital cortical alterations and spina bifida. Downward displacement of the cerebellum causes hydrocephalus in the most severely impaired cases. Although the involvement of polycomb genes in human disease is starting to be recognized, this is the first demonstration of their role in nervous system malformations. Our work strongly suggests that brain malformations such as CM can result from altered epigenetic regulation of genes involved in cell proliferation in the brain.


Vaginitis emphysematosa. A report of four cases.
It has been hypothesized that vaginitis emphysematosa is a manifestation of trichomonal or Gardnerella infection. In support of this etiologic concept, four cases of the disorder are described showing the apparent curative effect of treating the associated infection. The linkage of these and other reported cases with conditions of impaired immunity suggests that immunologic factors are involved in the pathogenesis.


Clinical relevance of the distinction between alcohol dependence with and without a physiological component.
DSM-IV indicates that diagnoses of substance dependence should be further characterized with regard to the presence of a physiological component, defined by tolerance or withdrawal. This study evaluated the possible meaning of this distinction in alcohol-dependent men and women. As part of the Collaborative Study on the Genetics of Alcoholism, structured interviews were carried out with 3,395 DSM-III-R-defined alcohol-dependent individuals divided into 2,949 subjects (86.9%) with evidence of tolerance and/or withdrawal (group 1), 51.3% of whom evidenced withdrawal symptoms, and 446 subjects (13.1%) without a physiological component (group 2). Data were evaluated to determine differences between the two groups. Group 1 reported greater severity of alcohol dependence as demonstrated by a larger maximum number of drinks in 24 hours, more persons reporting binges, more alcohol-related life problems, more relevant DSM-III-R criteria endorsed, more physiological complications, and more alcohol-related emotional/psychiatric symptoms such as depression and anxiety. Each of these severity indicators for problems in group 1 was significant in the presence of the others in a logistic regression, and similar items remained significant when tolerance alone, withdrawal alone, or their combination was used as the criterion for group 1 membership; however, for withdrawal a larger proportion of the variance was explained by the predictor variables. The regression results were independent of gender, proband status, and history of antisocial personality disorder. The results support the clinical relevance of distinguishing between alcohol-dependent patients with and without a physiological component. The data indicate a potential advantage to limiting that definition to withdrawal only.


Surveillance of Genetic Variations Associated with Antimalarial Resistance of Plasmodium falciparum Isolates from Returned Migrant Workers in Wuhan, Central China.
Antimalarial drug resistance developed in Plasmodium falciparum has become a problem for malaria control. Evaluation of drug resistance is the first step for effective malaria control. In this study, we investigated the gene mutations of P. falciparum using blood samples from returned Chinese migrant workers in order to identify drug resistance-associated molecular markers. These workers returned from Africa and Southeast Asia (SEA) during 2011 to 2016. Polymorphisms in pfcrt, pfmdr1, and k13-propeller genes and the haplotype patterns of Pfcrt and Pfmdr1 were analyzed. The results showed the presence of four haplotypes of Pfcrt codons 72 to 76, including CVMNK (wild type), SVMNT and CVIET (mutation types), and CV M/I N/E K/T (mixed type), with 50.57%, 1.14%, 25.00%, and 23.30% prevalence, respectively. For Pfmdr1, N86Y (22.28%) and Y184F (60.01%) were the main prevalent mutations (mutations are underlined). The prevalence of mutation at position 550, 561, 575, and 589 of K13-propeller were 1.09%, 0.54%, 0.54%, and 0.54%, respectively. These data suggested that Pfcrt, Pfmdr1, and K13-propeller polymorphisms are potential markers to assess drug resistance of P. falciparum in China, Africa, and SEA.


Effect of Foot Manipulation on Pregnancy-Related Pelvic Girdle Pain: A Feasibility Study.
The objective of this study was to investigate if the research process to evaluate the effect of foot manipulation on pregnancy-related pelvic girdle pain (PPGP) is feasible. A randomized, single-blind (patients and evaluators) pilot trial was performed to compare foot manipulation to a comparative group at 6-weekly treatment sessions at 5 physiotherapy outpatient clinics in Skaraborg primary care (Skövde, Sweden). Women at 12 to 31 weeks of pregnancy with well-defined PPGP (n = 97) and joint dysfunction or decreased range of movement in the feet were included. Women with a twin pregnancy, low back pain, rheumatoid arthritis, or other serious diseases and those who had previous foot manipulation were excluded. Visual analog scale scores were recorded before study start, before and after each treatment session, and 3 months after delivery. One-hundred and two women were eligible, and 97 were included (group 1: foot manipulation, n = 47; group 2: comparative treatment, n = 50); 40 and 36 in the foot manipulation and comparative treatment groups, respectively, completed the study. The foot manipulation group had a nonsignificant pain relief score compared with that of the comparative group, which had higher pain relief scores. The difference was most pronounced at the first and second treatment sessions. A power analysis showed that at least 250 individuals would be needed in each group to confirm the effect of foot manipulation. This study showed that it is feasible to assess the effect of foot manipulation on PPGP in a multicenter physical therapy outpatient clinic setting. A new larger study should choose a different comparative method and test this hypothesis in a full-scale trial.


Closeness and separation in neonatal intensive care.
In this paper, we highlight the need for acknowledging the importance and impact of both physical and emotional closeness between the preterm infant and parent in the neonatal intensive care unit. Physical closeness refers to being spatially close and emotional closeness to parental feelings of being emotionally connected to the infant (experiencing feelings of love, warmth and affection). Through consideration of the literature in this area, we outline some of the reasons why physical closeness and emotional closeness are crucial to the physical, emotional and social well-being of both the infant and the parent. These include positive effects on infant brain development, parent psychological well-being and on the parent-infant relationship. The influence of the neonatal unit environment and culture on physical and emotional closeness is also discussed. Culturally sensitive care practices, procedures and the physical environment need to be considered to facilitate parent-infant closeness, such as through early and prolonged skin-to-skin contact, family-centred care, increased visiting hours, family rooms and optimization of the space on the units. Further research is required to explore factors that facilitate both physical and emotional closeness to ensure that parent-infant closeness is a priority within neonatal care.


Parental work schedules and child overweight and obesity.
Studies in school-age children have consistently shown a positive association between maternal paid work hours and child obesity. However, there is conflicting evidence about the impact of maternal work hours scheduled at nonstandard times (for example, evenings, nights or weekends), and no previous examination of paternal work schedules and child weight. We examined the associations between maternal, paternal and combined parental paid work schedules and overweight/obesity in children at age 9 years. Data were analysed from the most recent follow-up of 9-year-old children (n=434) in an Australian birth cohort study. Children were measured and classified as overweight/obese using the International Obesity Taskforce body mass index cutoff points. Current working conditions of parents were obtained from a structured interview with the primary caregiver. Logistic regression analyses were used to investigate the effect of parental work schedules on child overweight/obesity with adjustment for a range of sociodemographic and household factors associated with parental employment and child weight. At 9 years of age, 99 children (22.8%) were overweight or obese. When parental work schedules were examined separately, child overweight/obesity was significantly associated with paternal nonstandard work schedules (adjusted odds ratio (OR) 1.97, 95% confidence interval (CI) 1.08-3.61). There was no association with any type of maternal work schedule. We also found an association between child overweight/obesity and circumstances in which both parents worked nonstandard schedules; however, this was of borderline statistical significance in the adjusted models (adjusted OR 2.26, 95% CI 0.99-5.16). Work hours scheduled at nonstandard times, when worked by the father or both parents, were associated with child overweight and obesity. These findings indicate the potential importance of fathers' paid work arrangements for child overweight/obesity, which until recently has largely been ignored.


Gut Microbiota Linked to Sexual Preference and HIV Infection.
The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n = 156) and Stockholm (n = 84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction.


Rheumatic diseases and pregnancy: a perspective.
The interaction between certain rheumatic diseases, sex hormones and their wide fluctuation during pregnancy and postpartum may be responsible for the variable course of rheumatic diseases during pregnancy. Important issues include effects on the mother and fetus by the disease, pregnancy and maternal drug therapy.


The GABAA receptor gene family: new opportunities for drug development.
gamma-Aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian brain, exerts its effects through the activation of a ligand-gated ion channel, the GABAA receptor, leading to the inhibition of the activity of neurons. A family of GABAA receptors has been identified, some of which are targets for therapeutic agents such as benzodiazepines, barbiturates and general anesthetics. Recently, novel transgenic approaches have been used to understand the function of receptor subtypes and, thereby, their therapeutic utility. Additionally, progress has been made in the development of novel receptor subtype-selective compounds. In this review, we will primarily focus on progress achieved in the understanding of the function of this receptor family, and potential exploitation for drug development.


Caries experience and treatment needs among Albanian 12-year-olds.
To determine the dental caries experience and treatment needs among 12-year-olds in Albania. This 2011 cross sectional survey used cluster sampling with DMFT and SiC indexes used to assess dental caries experience; DT/DMFT to assess untreated caries; FT/DMFT the care index and MT/DMFT as missing index. 1928 12-year-olds selected from state schools across 16 local districts with a mix of urban and rural areas and contrasting socio-economic groups. WHO protocols were used. The caries prevalence (DMFT > 0) was 87% (95%CI 85.6,88.4) and 29.6% were without cavitated carious lesions (DT = 0). The mean caries experience (DMFT) was 3.73 (sd 2.71) for boys, 3.71 (sd 2.61, p = 0.88) for girls and 3.72 (sd 2.66) overall. The caries treatment needs DT/DMFT was 56% (sd 0.36), the mean FT/DMFT (Care Index) was 31% (sd 0.34) and the mean SiC index was 6.72 (sd 1.92). Dental caries experience and untreated dental caries were high compared with 12-year-olds in most European Union Member States. This suggests an urgent need for a national preventive program and improved access to oral care for this age group.


1H and 13C HR-MAS spectroscopy of intact biopsy samples ex vivo and in vivo 1H MRS study of human high grade gliomas.
High-resolution magic angle spinning (HR-MAS) one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy has been used to study intact glioblastoma (GBM) brain tumour tissue. The results were compared with in vitro chemical extract and in vivo spectra. The resolution of 1H one-dimensional, 1H TOCSY and 13C HSQC HR-MAS spectra is comparable to that obtained on perchloric extracts. 13C HSQC HR-MAS spectra have been particularly useful for the identification of 37 different metabolites in intact biopsy tumours, excluding water and DSS components. To our knowledge, this is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular in brain tumour tissue. Tissue degradation during the recording of the NMR experiment was avoided by keeping the sample at a temperature of 4 degrees C. Detailed metabolical compositions of 10 GBM (six primary, two secondary and two unclassified) were obtained. A good correlation between ex vivo and in vivo MRS has been found.


Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action.
Ketamine is an anesthetic drug that is also used for off-label indications such as the mediation of analgesia and sedation in various settings. It is additionally recognized as an agent with antidepressant potential. For depression, it is most commonly administered as a slow intravenous infusion in subanesthetic doses (usually 0.5 mg/kg). As an antidepressant, is strikingly different from conventional antidepressant drugs in that it brings about rapid and marked attenuation of depressive symptoms even in patients with refractory depression. The benefits are observed within hours of administration, peak after about a day, and are lost 3-12 days later. Patients who do not benefit after the initial dose may benefit with serial dosing or at higher doses. Benefits can be maintained for weeks to months by the continuation of ketamine sessions at 2- to 4-day intervals. Adverse effects include dissociative and psychotomimetic changes that are almost always mild and transient, if present; transient elevation of heart rate and blood pressure often occur. These changes are usually well tolerated and are very seldom responsible for treatment discontinuation. Whereas ketamine is an N-methyl-d-aspartate receptor antagonist, and whereas much is known about its different biological effects, its actions that mediate the antidepressant response are presently not known for certain. Although big data on ketamine are presently unavailable, the drug holds promise in the treatment of depression, especially refractory depression.


Human Monocyte Subset Distinctions and Function: Insights From Gene Expression Analysis.
Monocytes are a highly plastic innate immune cell population that displays significant heterogeneity within the circulation. Distinct patterns of surface marker expression have become accepted as a basis for distinguishing three monocyte subsets in humans. These phenotypic subsets, termed classical, intermediate and nonclassical, have also been demonstrated to differ in regard to their functional properties and disease associations when studied in vitro and in vivo. Nonetheless, for the intermediate monocyte subset in particular, functional experiments have yielded conflicting results and some studies point to further levels of heterogeneity. Developments in genetic sequencing technology have provided opportunities to more comprehensively explore the phenotypic and functional differences among conventionally-recognized immune cell subtypes as well as the potential to identify novel subpopulations. In this review, we summarize the transcriptomic evidence in support of the existence of three separate monocyte subsets. We also critically evaluate the insights into subset functional distinctions that have been garnered from monocyte gene expression analysis and the potential utility of such studies to unravel subset-specific functional changes which arise in disease states.


Software for the Diagnosis of Sarcopenia in Community-Dwelling Older Adults: Design and Validation Study.
The usual diagnosis of sarcopenia requires a dual-energy x-ray absorptiometry (DXA) exam, which has low accessibility in primary care for Latin American countries. The aim of this study is to design and validate software for mobile devices (Android, IOS) and computers, based on an adapted version of the diagnostic algorithm of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). Follow-up exams were conducted on 430 community-dwelling Chileans 60 years and older (mean 68.2 years, SD 4.9) participating in the IsaMayor and Alexandros cohorts designed to study sarcopenia and disability associated with obesity, respectively. All the participants from the cohorts were randomly selected from the registries of primary health care centers and, for this study, must have a DXA scan at baseline. The software (HTSMayor) was designed according to an adapted version of the algorithm proposed by the EWGSOP and was divided into four phases: longitudinal validation of diagnostic algorithm of sarcopenia, alpha version, beta version, and release version. The software estimates appendicular skeletal muscle mass (ASM) using an anthropometric equation or DXA measurements with Chilean cut-off points. The predictive validation of the algorithm was estimated, comparing functional limitations (at least one activity of daily living, two instrumental activities of daily living, or three mobility limitations), falls, and osteoporosis at follow-ups in patients with and without sarcopenia at baseline, using adjusted logistic models. After a median follow-up of 4.8 years (2078.4 person-years), 37 (9.9%) new cases of sarcopenia, out of the 374 patients without sarcopenia at baseline, were identified (incidence density rate=1.78 per 100 person-years). ASM estimated with the anthropometric equation showed both a high sensitivity and specificity as compared with those estimated by DXA measurements, yielding a concordance of 0.96. The diagnostic algorithm of sarcopenia considered in the software with the equation showed both a high sensitivity (82.1%) and specificity (94.9%) when compared with DXA (reference standard). Adults without sarcopenia (at baseline) showed better physical performance (after approximately 5 years) than adults with sarcopenia. Loss of functionality was greater in adults with sarcopenia (OR 5.0, 95% CI 2.2-11.4) than in adults without sarcopenia. In addition, the risks of falls (OR 2.2, 95% CI 1.1-4.3) and osteoporosis (OR 2.8, 95% CI 1.2-6.6) were higher in older persons with sarcopenia than those without sarcopenia. The measurements and results were completed for the beta and release tests with a mean time of 10 minutes and 11 minutes, respectively. We developed and validated a software for the diagnosis of sarcopenia in older Chilean adults that can be used on a mobile device or a computer with good sensitivity and specificity, thus allowing for the development of programs for the prevention, delay, or reversal of this disease. To our knowledge, HTSMayor is the first software to diagnose sarcopenia. RR2-10.2196/13657.


Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia.
Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to examine the role of pancreatic islets in Cd-induced hyperglycemia. Male Sprague-Dawley rats were given daily subcutaneous doses of Cd at 0.6 mg/kg over 12 weeks. There was a resulting time-dependent increase in fasting blood glucose and altered insulin release in vitro. Islets isolated from control (saline-treated) and Cd-treated animals were incubated in low (0.5 mg/mL) or high (3 mg/mL) glucose conditions. Islets from 12 week Cd-treated animals had significantly less glucose-stimulated insulin release compared to islets from saline-treated control animals. The actual Cd content of isolated islets was 5 fold higher than the whole pancreas (endocrine + exocrine) and roughly 70% of that present in the renal cortex. Interestingly, islets isolated from Cd-treated animals and incubated in high glucose conditions contained significantly less Cd and zinc than those incubated in low glucose. These results show that within whole pancreatic tissue, Cd selectively accumulates in pancreatic islets and causes altered islet function that likely contributes to dysglycemia.


Treatment of established bone loss after renal transplantation with etidronate.
Osteoporosis is a well-documented complication of organ transplantation. Bisphosphonates have been shown to be effective in preventing corticosteroid-induced osteoporosis in renal transplant recipients, but data are lacking for treatment of established osteoporosis. This study reports our clinical experience of treatment with the bisphosphonate etidronate in a single renal transplant center. To establish the effectiveness of etidronate in treating established low bone mineral density (BMD), all newly transplanted patients treated with etidronate were compared with controls. Twenty-five patients treated with etidronate (14 males, 11 females) and 24 controls (15 males, 9 females) were identified from the cohort of patients who underwent transplantation between January 1, 1994, and December 31, 1996. There was no difference in mean age, weight, or cumulative dose of corticosteroids between the treatment and control groups. The baseline BMD measurement was performed at 10.4 +/- 5.3 months after transplantation for treated patients and at 10.7 +/- 4.5 months for controls (P=0.78). Over the subsequent 1-year study period, patients treated with etidronate demonstrated a greater increase in BMD at sites with a preponderance of trabecular bone. Lumbar spine BMD increased 4.3 +/- 6.1% in the treatment group versus 0.55 +/ -5.3% in controls (P<0.03) and trochanter BMD increased 10.3 +/- 11.9% and 2.2 +/- 5.7%, respectively, in the treatment and control groups (P<0.02). This study establishes the effectiveness of etidronate for treatment of low BMD in renal transplant recipients. Patients selected for treatment had lower baseline BMD than control subjects, yet still showed a clinically important increase in BMD.


Recognition and Surgical Management of Aberrant Right Hepatic Duct Originating From the Cystic Duct.
An aberrant right hepatic duct is a rare congenital anomaly of the biliary system. Failure to recognize these anomalies can result in serious complications. In this case, we present a patient who underwent laparoscopic cholecystectomy for chronic cholecystitis. Post-operatively she developed a bile leak for which she underwent reoperation. On re-exploration, she was discovered to have a cystic stump leak and a rare Hisatsugu type V anatomic anomaly of the right hepatic duct originating from the cystic duct. She was subsequently managed with oversewing of the cystic duct stump and drainage. This case demonstrates the importance of recognizing these rare anomalies and the challenges of management in a rural, resource-limited setting.


Hepatoprotective potential of Tecomella undulata stem bark is partially due to the presence of betulinic acid.
Tecomella undulata (TU;` Family Bignoniaceae) is used in Indian Ayurvedic system of medicine for treating various diseases including hepatic ailments. It is also incorporated in various marketed hepatoprotective polyherbal formulations. The present study was aimed at evaluating possible hepatoprotective role of isolated compounds from TU stem bark (TSB) using in vitro and in vivo experimental models. In vitro cytotoxicity and hepatoprotective potential of various extract, fractions and isolated compounds from TU stem bark were evaluated using HepG2 cells. Rats were pre-treated with TU methanolic extract (TSB-7) or betulinic acid (MS-2) or silymarin for 7 days followed by a single dose of CCl(4) (0.5 ml/kg, i.p.). Plasma markers of hepatic damage, hepatic antioxidants and indices of lipid peroxidation along with microscopic evaluation of liver were assessed in control and treatment groups. TSB-2 and MS-1 accounted for significant cell death whereas; TSB-1, TBS-7, TSB-9, TSB-10 and, MS-2 did not register significant cytotoxicity. Further, non-cytotoxic components exhibited ascending grade of hepatoprotection in vitro (TSB-10<TSB-1<TSB-7<TSB-9<MS-2). Pre-treatment of TSB-7 or MS-2 to CCl(4) treated rats prevented hepatocyte damage as evidenced by biochemical and histopathological observations. It can be concluded that, hepatoprotective potential of Tecomella undulata stem bark is partially due to the presence of betulinic acid.


Glass transition of polymers in bulk, confined geometries, and near interfaces.
When cooled or pressurized, polymer melts exhibit a tremendous reduction in molecular mobility. If the process is performed at a constant rate, the structural relaxation time of the liquid eventually exceeds the time allowed for equilibration. This brings the system out of equilibrium, and the liquid is operationally defined as a glass-a solid lacking long-range order. Despite almost 100 years of research on the (liquid/)glass transition, it is not yet clear which molecular mechanisms are responsible for the unique slow-down in molecular dynamics. In this review, we first introduce the reader to experimental methodologies, theories, and simulations of glassy polymer dynamics and vitrification. We then analyse the impact of connectivity, structure, and chain environment on molecular motion at the length scale of a few monomers, as well as how macromolecular architecture affects the glass transition of non-linear polymers. We then discuss a revised picture of nanoconfinement, going beyond a simple picture based on interfacial interactions and surface/volume ratio. Analysis of a large body of experimental evidence, results from molecular simulations, and predictions from theory supports, instead, a more complex framework where other parameters are relevant. We focus discussion specifically on local order, free volume, irreversible chain adsorption, the Debye-Waller factor of confined and confining media, chain rigidity, and the absolute value of the vitrification temperature. We end by highlighting the molecular origin of distributions in relaxation times and glass transition temperatures which exceed, by far, the size of a chain. Fast relaxation modes, almost universally present at the free surface between polymer and air, are also remarked upon. These modes relax at rates far larger than those characteristic of glassy dynamics in bulk. We speculate on how these may be a signature of unique relaxation processes occurring in confined or heterogeneous polymeric systems.


Femtosecond fiber Bragg grating fabrication with adaptive optics aberration compensation.
We present fiber Bragg gratings (FBGs) fabricated using adaptive optics aberration compensation for the first time to the best of our knowledge. The FBGs are fabricated with a femtosecond laser by the point-by-point method using an air-based objective lens, removing the requirement for immersion oil or ferrules. We demonstrate a general phase correction strategy that can be used for accurate fabrication at any point in the fiber cross-section. We also demonstrate a beam-shaping approach that nullifies the aberration when focused inside a central fiber core. Both strategies give results which are in excellent agreement with coupled-mode theory. An extremely low wavelength polarization sensitivity of 4 pm is reported.


Identification and sequence of the gene encoding cytochrome c heme lyase in the yeast Saccharomyces cerevisiae.
Mitochondrial cytochrome c contains a heme group covalently attached through thioether linkages to two cysteinyl residues of the protein. We demonstrate here that the nuclear gene, CYC3, in the yeast Saccharomyces cerevisiae, encodes cytochrome c heme lyase (CCHL), the enzyme catalyzing the attachment of heme to apocytochrome c. Mitochondrial extracts from cyc3- mutants are deficient in CCHL activity compared with extracts from normal strains, whereas strains carrying multiple copies of the CYC3 gene exhibit high levels of the activity. The CYC3 gene was cloned by functional complementation of a cyc3- mutant using a previously isolated plasmid containing the gene PYK1, which is tightly linked to CYC3. An open reading frame encoding a protein of 269 amino acids was identified from the DNA sequence of a fragment encompassing the CYC3 gene, and the corresponding transcript shown to be approximately 0.9 kb in length. CCHL appears to be a single polypeptide chain which acts specifically on the two forms of cytochrome c, but not on cytochrome c1.


[The hemostatic system in patients with pulmonary tuberculosis during their preparation for surgery].
The basic mechanisms responsible for equilibrium impairment in the hemostatic system in pulmonary tuberculosis patients are reduced activity of antithrombin III and disturbances of platelet functional capacities. These changes were proved to reflect the course of intravascular hemocoagulation whose degree of manifestation is related directly to the extent of specific lesions in the lungs and intoxication phenomena. The process of intravascular hemocoagulation in tuberculosis patients runs in the presence of an increased concentration of plasma fibronectin , while major surgery performed in patients with fibrous-cavernous processes leads to its reduced level. It is pathogenetically proved to use antithrombin III concentrate preparations with anti- and dysaggregatory properties, fibronectin preparations, trasylol or its analogs during complex preoperative preparation of patients.


Electrochemical studies of silver nanoparticles: a guide for experimentalists and a perspective.
This perspective summarises four different electrochemical techniques that have been established and frequently used to characterize various properties of silver nanoparticles. These are based on drop casting (I), in situ nanoparticle sticking and stripping (II), transfer sticking and stripping (III) or nanoparticle impacts (IV). The specific characteristics of the different methodologies are explained and contrasted with each other with the focus being on the respective benefits and limitations together with essential insights for experimentalists.


Reproductive history and progressive multiple sclerosis risk in women.
Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case-control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48-52) and controls (median, interquartile range: 51 years, 49-53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1-3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R 2 = 0.359, P < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1-3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R 2 = 0.229, P < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a 'dose effect' of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.


New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis.
Oral anticoagulation in addition to antiplatelet treatment after an acute coronary syndrome might reduce ischaemic events but increase bleeding risk. We performed a meta-analysis to evaluate the efficacy and safety of adding direct thrombin or factor-Xa inhibition by any of the novel oral anticoagulants (apixaban, dabigatran, darexaban, rivaroxaban, and ximelagatran) to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy in this setting. All seven published randomized, placebo-controlled phase II and III studies of novel oral anticoagulants in acute coronary syndromes were included. The database consisted of 30 866 patients, 4135 (13.4%) on single, and 26 731 (86.6%) on dual antiplatelet therapy, with a non-ST- or ST-elevation acute coronary syndrome within the last 7-14 days. We defined major adverse cardiovascular events (MACEs) as the composite of all-cause mortality, myocardial infarction, or stroke; and clinically significant bleeding as the composite of major and non-major bleeding requiring medical attention according to the study definitions. When compared with aspirin alone the combination of an oral anticoagulant and aspirin reduced the incidence of MACE [hazard ratio (HR) and 95% confidence interval 0.70; 0.59-0.84], but increased clinically significant bleeding (HR: 1.79; 1.54-2.09). Compared with dual antiplatelet therapy with aspirin and clopidogrel, adding an oral anticoagulant decreased the incidence of MACE modestly (HR: 0.87; 0.80-0.95), but more than doubled the bleeding (HR: 2.34; 2.06-2.66). Heterogeneity between studies was low, and results were similar when restricting the analysis to phase III studies. In patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy.


Incidence rates of malignancies and hospitalized infectious events in patients with psoriasis with or without treatment and a general population in the U.S.A.: 2005-09.
Rates of malignancies and hospitalized infectious events (HIEs) among psoriasis patients are higher than in the general population, but it is unclear if higher rates are associated with the underlying inflammatory state, treatments or both. To assess the incidence of malignancies and HIEs in a healthy US population, a psoriasis population, and four treated psoriasis populations. Using a US claims database, we identified a general population, a psoriasis cohort, and four treatment cohorts [non-biologic systemics, etanercept, other TNF blockers (adalimumab, infliximab) and phototherapy] to assess the incidence of lymphomas, nonmelanoma skin cancer (NMSC), all malignancies (excluding NMSC), and HIEs, standardized for age and sex. Among 40 987 patients with psoriasis, 11% were prescribed non-biologics, 15% etanercept, 6% other TNF blockers and 11% phototherapy. For all cancers, the psoriasis population rate (114/10 000 person-years) was 20% greater than the rate found in the general population (95/10 000 person-years). For NMSC, the psoriasis population rate (129/10 000 person-years) was 65% greater than the general population rate (78/10 000 person-years). The incidence rate for each treatment modality was lower than the overall psoriasis cohort, except for phototherapy. There was little difference in the rates of lymphomas. NMSC rates were higher among patients treated with phototherapy. HIE rates ranged from 165/10 000 person-years for the phototherapy group to 262/10 000 person-years for the other anti-TNF group. Patients with psoriasis appear to have higher rates of malignancy and HIE than the general population, with little difference in rates between the treatment methods, except for a higher rate of cancer among those receiving phototherapy.


[Physiology of nodal tissue and effect of products used in anesthesia].
The three fundamental properties of the nodal tissue, i.e.: excitability, automaticity and conduction of the depolarisation wave, are directly dependent on ionic transmembrane currents. These currents, either active or passive, determine the characteristics of the membrane action potential. Passive ionic movements cross gated transmembrane channels which activation is voltage-dependent, sometimes time-dependent and, for Ca2+ channels, dependent on intra-cellular cyclic AMP content. Both intra and extra-cellular ionic concentrations (K+, Ca2+, Mg2+) alter these passive movements. Active ionic movements require ATP hydrolysis and depend only on cellular metabolism. The neurovegetative system and its transmitters modulate the nodal tissue function altering passive ionic currents. Drugs employed during anesthesia change this function either by direct action on the ionic currents or by indirect action on the neurovegetative system or on histamine liberation. Thus: local anesthetics block selectively fast sodium channels; halogenated volatile anesthetics inhibit slow calcium channels: and narcotics are quite always vagomimetics, sometimes sympathicolytics, they often release histamine. Nevertheless, mechanism of action of various drugs remain unclear.


Spatiotemporal scales and links between electrical neuroimaging modalities.
Recordings of brain electrophysiological activity provide the most direct reflect of neural function. Information contained in these signals varies as a function of the spatial scale at which recordings are done: from single cell recording to large scale macroscopic fields, e.g., scalp EEG. Microscopic and macroscopic measurements and models in Neuroscience are often in conflict. Solving this conflict might require the developments of a sort of bio-statistical physics, a framework for relating the microscopic properties of individual cells to the macroscopic or bulk properties of neural circuits. Such a framework can only emerge in Neuroscience from the systematic analysis and modeling of the diverse recording scales from simultaneous measurements. In this article we briefly review the different measurement scales and models in modern neuroscience to try to identify the sources of conflict that might ultimately help to create a unified theory of brain electromagnetic fields. We argue that seen the different recording scales, from the single cell to the large scale fields measured by the scalp electroencephalogram, as derived from a unique physical magnitude--the electric potential that is measured in all cases--might help to conciliate microscopic and macroscopic models of neural function as well as the animal and human neuroscience literature.


An anatomic study of the distal femoral epiphysis.
The anatomy of the undulating distal femoral physis may be relevant to growth disturbance after physeal fractures and screw fixation about the physis. The surface anatomy of this physis has not been well described. We performed an anatomic study on 26 cadaveric distal femoral epiphyses in specimens 3 to 18 years of age. High-resolution 3-dimensional surface scans were obtained and analyzed to determine the heights, approximate surface areas, and locations of the major undulations. Gross examination revealed lateral and anteromedial peripheral notches at the metaphyseal-epiphyseal junction, which deepen with advancing skeletal maturity. Within the epiphysis, there are 3 major undulations: a central ridge, lateral ridge, and medial peak, with mean heights of 5.5 mm (range, 2.9 to 9.8 mm), 2.5 mm (1.0 to 5.7 mm), and 2.9 mm (0.9 to 4.7 mm), respectively. The normalized height and surface area of each undulation decreased with increasing age, most dramatically in the central ridge. With respect to a line connecting the medial and lateral aspects of the physis, we found that the central peak passes more superior with younger age, and tends to be more posteriorly located. The lowest point of the physis is located either anteromedial or posterolateral. The central ridge, lateral ridge, and medial peak are the 3 major undulations in the distal femoral physis. The central ridge has the greatest height and most dramatic decrease in relative size with increasing age, suggesting structural importance. This anatomic data can guide metaphyseal and epiphyseal screw fixation. This study provides quantitative data on the topographic anatomy of the distal femoral physis, which can guide screw placement about the physis. These data may help identify fractures patterns with a greater risk of growth disturbance and key radiographic landmarks for guiding fracture reduction.


Headache in Idiopathic Intracranial Hypertension: Findings From the Idiopathic Intracranial Hypertension Treatment Trial.
To characterize the phenotype, headache-related disability, medical co-morbidities, use of symptomatic headache medications, and headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Patients with untreated IIH and mild vision loss enrolled in the IIHTT and randomized to acetazolamide (ACZ) and weight loss or placebo (PLB) and weight loss had prospective assessment of headache disability using the Headache Impact Test-6 (HIT-6) questionnaire. Subjects with headache at the baseline visit were assigned a headache phenotype using the International Classification for Headache Disorders version 3 beta (ICHD-3b). Medication overuse was determined using the participants' reported medication use for the preceding month and ICHD-3b thresholds for diagnosing medication overuse headache. We investigated relationships between headache disability and various other clinical characteristics at baseline and at 6 months. Headache was present in 139 (84%) of the 165 enrollees at baseline. The most common headache phenotypes were migraine (52%), tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%). Fifty-one (37%) participants overused symptomatic medications at baseline, most frequently simple analgesics. A similar amount of improvement in the adjusted mean (± standard error) HIT-6 score occurred in the ACZ (-9.56 ± 1.05) and PLB groups (-9.11 ± 1.14) at 6 months (group difference -0.45, 95% CI -3.50 to 2.60, P = .77). Headache disability did not correlate with any of the studies, variables of interest, which included: the lumbar puncture opening pressure at baseline or at 6 months, body mass index, the amount of weight lost, papilledema grade, perimetric mean deviation, or the use of hormonal contraception. Headache disability was significantly associated with patient-reported quality of life in the physical, mental, and visual domains. Headache was common, of varied character, disabling, and associated with poorer quality of life in our cohort of patients with mild visual impairment. The lack of correlation between headache disability and cerebrospinal fluid (CSF) pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension, and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.


Evaluating the effectiveness of an active strap for wearable robot: A Mechanical and Physiological Study.
Straps are the most commonly used elements in the wearable robotic field, where it is employed as a physical human robot interface (pHRI) between the wearable robot and wearer's body. The main role of the strap is to transmit power from the robot to the wearer by pressing and attaching onto specific body parts to reduce the relative motion. To maximize the efficiency and performance using the appropriate function, a high stiffness and tension is required in the strap. However, the continuous force applied by the strap on the wearer's body is one of the main factors that reduces the wearing comfort of the wearable robot. In this paper, an active strap applied to a hip orthosis is proposed to restrict the hip joint angle. The active strap was periodically controlled using the hip joint angle of the orthosis and was only tightened when the hip joint angle reached the target hip joint angle. The experimental results were then used to evaluate the performance of the proposed strap from a mechanical and physiological point of view. The results suggest that active strap is capable of effectively performing the tasks of a hip orthosis during periodic movement, demonstrating its potential use in wearable robots. Furthermore, the physiological response observed at the contact area during periodic strap tension can relieve discomfort caused by prolonged tension, thus enhancing the comfort of the wearable robot.


Individual fitness and phenotypic selection in age-structured populations with constant growth rates.
Powerful multiple regression-based approaches are commonly used to measure the strength of phenotypic selection, which is the statistical association between individual fitness and trait values. Age structure and overlapping generations complicate determinations of individual fitness, contributing to the popularity of alternative methods for measuring natural selection that do not depend upon such measures. The application of regression-based techniques for measuring selection in these situations requires a demographically appropriate, conceptually sound, and observable measure of individual fitness. It has been suggested that Fisher's reproductive value applied to an individual at its birth is such a definition. Here I offer support for this assertion by showing that multiple regression applied to this measure and vital rates (age-specific survival and fertility rates) yields the same selection gradients for vital rates as those inferred from Hamilton's classical results. I discuss how multiple regressions, applied to individual reproductive value at birth, can be used efficiently to estimate measures of phenotypic selection that are problematic for sensitivity analyses. These include nonlinear selection, components of the opportunity for selection, and multilevel selection.


Stellated polyhedral assembly of a topologically complicated Pd4L4 'Solomon cube'.
Metallosupramolecular chemistry relies on self-assembly processes in which complicated species form through labile dative-covalent interactions. Two remarkable areas of this chemistry are the synthesis of topologically complicated threaded assemblies and of three-dimensional (3D) polyhedral assemblies. Very few polyhedral 3D metallosupramolecular assemblies show threaded motifs within them. Here we report an example of a new type of threaded 3D metallosupramolecular assembly built from four organic ligands and four palladium ions, a Pd(4)L(4) so-called 'Solomon's cube' in which interweaving and twisting of the ligands form both Solomon's links and figure-of-eight ring motifs. In the solid state, six of these Pd(4)L(4) tetramers assemble into a hollow spheroid that closely resembles a stellated truncated hexahedron.


External validation of a clinical scoring system for hematuria.
The aim of this study was to evaluate the accuracy of a new scoring system in Korean patients with hematuria at high risk of bladder cancer. A total of 319 consecutive patients presenting with painless hematuria without a history of bladder cancer were analyzed, from the period of August 2012 to February 2014. All patients underwent clinical examination, and 22 patients with incomplete data were excluded from the final validation data set. The scoring system included four clinical parameters: age (≥50 = 2 vs. <50 =1), gender (male = 2 vs. female = 1), history of smoking (smoker/ex-smoker = 4 vs. non-smoker = 2) and nature of the hematuria (gross = 6 vs. microscopic = 2). The area under the receiver-operating characteristic curve (95% confidence interval) of the scoring system was 0.718 (0.655-0.777). The calibration plot demonstrated a slight underestimation of bladder cancer probability, but the model had reasonable calibration. Decision curve analysis revealed that the use of model was associated with net benefit gains over the treat-all strategy. The scoring system performed well across a wide range of threshold probabilities (15%-45%). The scoring system developed is a highly accurate predictive tool for patients with hematuria. Although further improvements are needed, utilization of this system may assist primary care physicians and other healthcare practitioners in determining a patient's risk of bladder cancer.


Bioremediation of a Common Product of Food Processing by a Human Gut Bacterium.
Dramatic increases in processed food consumption represent a global health threat. Maillard reaction products (MRPs), which are common in processed foods, form upon heat-induced reaction of amino acids with reducing sugars and include advanced glycation end products with deleterious health effects. To examine how processed foods affect the microbiota, we fed gnotobiotic mice, colonized with 54 phylogenetically diverse human gut bacterial strains, defined sugar-rich diets containing whey as the protein source or a matched amino acid mixture. Whey or ϵ-fructoselysine, an MRP in whey and many processed foods, selectively increases Collinsella intestinalis absolute abundance and induces Collinsella expression of genomic loci directing import and metabolism of ϵ-fructoselysine to innocuous products. This locus is repressed by glucose in C. aerofaciens, whose abundance decreases with whey, but is not repressed in C. intestinalis. Identifying gut organisms responding to and degrading potentially harmful processed food components has implications for food science, microbiome science, and public health.


Coherent beam superposition of ten diode lasers with a Dammann grating.
We demonstrate the use of a binary diffractive optical element in a very simple setup to convert the multilobed beam from a low fill factor array of coherent laser diodes into a quasi-Gaussian beam. The phase profile of the grating is determined with a phase retrieval algorithm. Experimentally, the conversion efficiency reaches more than 44%. We also establish that this setup can be used to make an effective measurement of the coherency of the laser array.


Novel imaging techniques in pulmonary hypertension.
Pulmonary hypertension is a life-shortening condition, which may be idiopathic but is more frequently seen in association with other conditions. Current guidelines recommend cardiac catheterization to confirm the diagnosis of pulmonary hypertension. Evidence suggests an increasing role for noninvasive imaging modalities in the initial diagnostic and prognostic assessment and evaluation of treatment response. In this review we examine the evidence for current noninvasive imaging methodologies: echocardiography computed tomography and MRI in the diagnostic and prognostic assessment of suspected pulmonary hypertension and explore the potential utility of modeling and machine-learning approaches. Noninvasive imaging allows a comprehensive assessment of patients with suspected pulmonary hypertension. It plays a key part in the initial diagnostic and prognostic assessment and machine-learning approaches show promise in the diagnosis of pulmonary hypertension.


Diagnostic performance of ultrasound in nonpalpable cryptorchidism: a systematic review and meta-analysis.
Ultrasound is frequently obtained during the presurgical evaluation of boys with nonpalpable undescended testes, but its clinical utility is uncertain. To determine the diagnostic performance of ultrasound in localizing nonpalpable testes in pediatric patients. English-language articles were identified by searching Medline, Embase, and the Cochrane Library. We included studies of subjects younger than 18 years who had preoperative ultrasound evaluation for nonpalpable testes and whose testis position was determined by surgery. Data on testis location determined by ultrasound and surgery were extracted by 2 independent reviewers, from which ultrasound performance characteristics (true-positives, false-positives, false-negatives, and true-negatives) were derived. Meta-analysis of 12 studies (591 testes) was performed by using a random-effects regression model; composite estimates of sensitivity, specificity, and likelihood ratios were calculated. Ultrasound has a sensitivity of 45% (95% confidence interval [CI]: 29-61) and a specificity of 78% (95% CI: 43-94). The positive and negative likelihood ratios are 1.48 (95% CI: 0.54-4.03) and 0.79 (95% CI: 0.46-1.35), respectively. A positive ultrasound result increases and negative ultrasound result decreases the probability that a nonpalpable testis is located within the abdomen from 55% to 64% and 49%, respectively. Significant heterogeneity limited the precision of these estimates, which was attributable to variability in the reporting of selection criteria, ultrasound methodology, and differences in the proportion of intraabdominal testes. Ultrasound does not reliably localize nonpalpable testes and does not rule out an intraabdominal testis. Eliminating the use of ultrasound will not change management of nonpalpable cryptorchidism but will decrease health care expenditures.


Tomographic inversion for sediment parameters in shallow water
This article discusses inversions for bottom geoacoustic properties using broadband acoustic signals obtained from explosive sources. The experimental data used for the inversions are SUS charge explosions acquired on a vertical hydrophone array during the Shelf Break Primer Experiment conducted south of New England in the Middle Atlantic Bight in August 1996. The SUS signals were analyzed for their time-frequency behavior using wavelets. The group speed dispersion curves were obtained from the wavelet scalogram of the SUS signals. A genetic algorithm (GA) was used for the inversion of sound speeds in the water column and compressional wave speeds in the sediment layers. The variations in the sound speeds in the water column were represented using empirical orthogonal functions (EOFs). A range-independent normal mode routine was used to construct the replica fields corresponding to the parameters. Comparison of group speeds for modes 1 to 9 and for a range of frequencies 8 to 200 Hz was used to arrive at the best parameter fit. An efficient hybrid optimization scheme using the GA and a Levenberg-Marquardt algorithm is presented. Linear perturbation methods were also used to "fine tune" the inversions and to obtain resolution and variance estimates. Analysis was also done to compute the degree of convergence of each of the parameters by explicitly calculating the Hessian matrices numerically. A posteriori estimation of mean and covariance was also done to obtain error estimates. Group speeds for the inverted sound speed fields provide an excellent match to the experimental data. The inverted sediment compressional speed profile compares well with in situ measurements.


Associations between primates and other mammals in a central Amazonian forest landscape.
Little information exists on mixed-species groups between primates and other mammals in Neotropical forests. In this paper, we describe three such associations observed during an extensive large-vertebrate survey in central Amazonia, Brazil. Mixed-species groups between a primate species and another mammal were observed on seven occasions between squirrel monkeys (Saimiri cf. ustus) and either South American coatis (Nasua nasua) or tayras (Eira barbara) and between brown capuchins (Cebus apella) and coatis. All associations were restricted to floodplain forest during its dry stage. We suggest that the associations involving the coatis are connected to foraging and vigilance but may be induced by a common alternative food resource at a time of food shortage.


Intraosseous meningioma mimicking osteosarcoma in an adolescent: a case report.
Intaosseous meningiomas (IM) are the one of the less frequent benign tumors of the skull. The etiology of IM has not been cleared yet. The frontoparietal and orbital regions are the most common locations for IM. The average age for IM diagnosis is 50.5. A 16-year-old girl with a right frontoparietal mass was referred to our outpatient clinic. Cranial CT revealed a mass lesion which resulted in expansion in the right parietal and posterior frontal bone, having lytic and sclerotic regions inside with accompanying irregular cortex in inner and outer tables of the calvarium. Prediagnosis was osteosarcoma according to the imaging studies and after the performed biopsy and consecutive surgery, the lesion was diagnosed as IM. Though CT with bone windows is often useful, it is not always diagnostic. Biopsy plays an important role in calvarial vault lesions for planning the treatment. In our case, malignant criteria in radiology did not match the benign histology revealed. Radiological preoperative misdiagnosis of meningioma is possible.


Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies.
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC.


Case Report: An Atypical Case of Post-Kala-Azar Dermal Leishmaniasis with Ulcers and Verrucous Lesions: Clinical and Therapeutic Implications.
About 75% cases of post-kala-azar dermal leishmaniasis (PKDL) occur in India. Although the classic description of PKDL is the progression from initial hypopigmented macular lesions to papules to plaques and nodular lesions, atypical morphologies are also seen and are easily missed or misdiagnosed. We report a case of a 27-year-old man who presented to us with multiple acral ulcers and verrucous lesions for 5 years. A diagnosis of PKDL was made based on slit skin smear, histopathology, and quantitative polymerase chain reaction. The patient was given combination therapy with four doses of liposomal amphotericin B and miltefosine 50 mg twice daily for 45 days. In this report, we discuss unusual morphologies of PKDL, the pathway to the diagnosis, and the therapeutic options available along with their efficacy.


[Nursing errors and the consequences. Results of a survey of nurses from inpatient care institutions].
Internationally, research on the consequences of errors caused by nurses is quite comprehensive. In contrast, the body of knowledge on the effects that errors have on the nurses themselves is rather small. It is well known that errors can have profoundly negative outcomes on nurses. In some cases, however, errors can have useful ramifications. This paper shows the research results of a representative cross-sectional survey that covers 1,100 nurses working in German hospitals and nursing homes and illustrates the effects of errors on them. Most participants in the sample mentioned feelings of regret/remorse and irritation/annoyance/stress as an effect when they made a mistake. More than half of the nurses state that they also learnt from their errors. Hospital nurses frequently suffer from psychological effects while nursing home nurses experience more often professional or legal consequences. With increasing age and professional experience the nurses indicate a lower error impact. The answers given by nurse assistants differ from those of nurses with a three-year training course. The results suggest an amount of stress that may reduce efficiency and increase susceptibility to mistakes and which, therefore, needs to be remedied.


Financial, operational issues entangle Medicaid managed care.
Federal and state governments may soon require provision of managed care to the Medicaid eligible segment of the community. HMO financial managers must develop financial and operational plans prior to entering into negotiations for the development of a contract with a state. Key financial and operational issues related to Medicaid aid categories, contracting with providers, general administration, and product design must be addressed to minimize financial risk.


Cell tropism predicts long-term nucleotide substitution rates of mammalian RNA viruses.
The high rates of RNA virus evolution are generally attributed to replication with error-prone RNA-dependent RNA polymerases. However, these long-term nucleotide substitution rates span three orders of magnitude and do not correlate well with mutation rates or selection pressures. This substitution rate variation may be explained by differences in virus ecology or intrinsic genomic properties. We generated nucleotide substitution rate estimates for mammalian RNA viruses and compiled comparable published rates, yielding a dataset of 118 substitution rates of structural genes from 51 different species, as well as 40 rates of non-structural genes from 28 species. Through ANCOVA analyses, we evaluated the relationships between these rates and four ecological factors: target cell, transmission route, host range, infection duration; and three genomic properties: genome length, genome sense, genome segmentation. Of these seven factors, we found target cells to be the only significant predictors of viral substitution rates, with tropisms for epithelial cells or neurons (P<0.0001) as the most significant predictors. Further, one-tailed t-tests showed that viruses primarily infecting epithelial cells evolve significantly faster than neurotropic viruses (P<0.0001 and P<0.001 for the structural genes and non-structural genes, respectively). These results provide strong evidence that the fastest evolving mammalian RNA viruses infect cells with the highest turnover rates: the highly proliferative epithelial cells. Estimated viral generation times suggest that epithelial-infecting viruses replicate more quickly than viruses with different cell tropisms. Our results indicate that cell tropism is a key factor in viral evolvability.


Problems of medical education in Pakistan.
Inspite of being the products of present system of medical education in Pakistan, the faculty members of Baqai University are generally dissatisfied with it. They have raised their concern on present medical education at various forums. This paper discusses the problems of medical education in Pakistan as elicited by the faculty members of Baqai Medical University. The importance of this study lies in the growing concern over deteriorating standards of our medical education and the strengthening belief that a change in the system of medical education is inevitable.


The role of antibody in rat renal allograft rejection. I. Absence of antibody to erythrocyte-associated antigens is associated with enhanced renal allograft survival.
Three biweekly infusions of a x 10(10) highly purified LEW (RT1l) erythrocytes (LEW-E) administered to BN (RT1n) rats commencing at 1 month of age failed to elicit alloantibody or cell-mediated cytotoxicity against LEW target cells. The magnitude of the proliferative response of lymphocytes taken from LEW-E-infused BN rats in unilateral mixed lymphocyte culture against LEW stimulator cells was identical to that of control BN lymphocytes. LEW renal grafts inserted in LEW-E-infused BN rats showed a markedly prolonged survival which was specific since Wistar (RT1u) renal allografts were acutely rejected. LEW kidneys grafted to unmodified and LEW-E-infused BN recipients elicited cytotoxic antibody responses to Ia-like antigens and cellular immune responses of identical magnitude and specificity. On the other hand, LEW renal grafts evoked hemagglutinating alloantibody in control BN recipients but failed to do so in LEW-E-infused BN recipients. This unresponsiveness to LEW-E-associated antigens was specific since Wistar renal grafts elicited anti-Wistar hemagglutinin responses in LEW-E-infused BN recipients. These results suggest that antibodies to LEW-E-associated alloantigens play an essential role in the acute rejection of LEW renal grafts by BN recipients.


Ultrasonic blood flow measurements: transcutaneous compared with implanted cuff.
Experiments were undertaken in our laboratory to establish relationships between flow parameters calculated from implanted ultrasonic cuff signals and those obtained with a transcutaneous probe. Analog signals were received from crystals surgically implanted on the right carotid, right femoral, and abdominal aorta of a mature male beagle dog. Near these locations, transcutaneous measurements were made using a prescribed technique. From these ultrasonic signals, the following time dependent flow parameters were calculated: spatial velocities, velocity profiles, diameters, flows, and velocity frequency distributions. Using these measurements, a comparison between the implanted cuff and transcutaneous probe was made. In addition to high reproductibility, results confirm a strong correlation between the two techniques; consequently, the validity of the less traumatic transcutaneous method is substantiated.


Disturbed Experience of Time in Depression-Evidence from Content Analysis.
Disturbances in the experience of time have been a commonly reported feature of depressive disorders since the beginning of modern psychiatry and psychological research. However, qualitative research approaches to investigate the phenomenon are rarely used. We employed content analysis to investigate disturbances of time experience in Major Depressive Disorder. Our analysis from 25 participants showed that individuals with Major Depressive Disorder subjectively seem to have lost the ability to influence or change the present, resulting in an impersonal and blocked future. The present is rendered meaningless, the past unchangeably negative, and the passage of time turned into a dragging, inexorable, and viscous continuance. The overall,-possibly intersubjective-concept of time experience, remains largely intact, causing or adding to depressive mood and suffering. We elaborate on how these findings reflect previous theories on the experience of time in depression. This study might encourage future inquiries into both the phenomenal and neuroscientific foundation of time experience under psychopathological conditions.


Cell-free expression of the outer membrane protein OprF of Pseudomonas aeruginosa for vaccine purposes.
Pseudomonas aeruginosa is the second-leading cause of nosocomial infections and pneumonia in hospitals. Because of its extraordinary capacity for developing resistance to antibiotics, treating infections by Pseudomonas is becoming a challenge, lengthening hospital stays, and increasing medical costs and mortality. The outer membrane protein OprF is a well-conserved and immunogenic porin playing an important role in quorum sensing and in biofilm formation. Here, we used a bacterial cell-free expression system to reconstitute OprF under its native forms in liposomes and we demonstrated that the resulting OprF proteoliposomes can be used as a fully functional recombinant vaccine against P. aeruginosa Remarkably, we showed that our system promotes the folding of OprF into its active open oligomerized state as well as the formation of mega-pores. Our approach thus represents an easy and efficient way for producing bacterial membrane antigens exposing native epitopes for vaccine purposes.


Fall prevention and bathroom safety in the epilepsy monitoring unit.
Falls are one of the most common adverse events occurring in the epilepsy monitoring unit (EMU) and can result in significant injury. Protocols and procedures to reduce falls vary significantly between institutions as it is not yet known what interventions are effective in the EMU setting. This study retrospectively examined the frequency of falls and the impact of serial changes in fall prevention strategies utilized in the EMU between 2001 and 2014 at a single institution. Overall fall rate was 2.81 per 1000 patient days and varied annually from 0 to 9.02 per 1000 patient days. Both seizures and psychogenic nonepileptic events occurring in the bathroom were more likely to result in falls compared with events occurring elsewhere in the room. With initiation of increased patient education, hourly nurse rounding, nocturnal bed alarms, having two persons assisting for high fall risk patients when out of bed, and immediate postfall team review between 2001 and 2013, there was a trend of decreasing fall frequency; however, no specific intervention could be identified as having a particular high impact. In late 2013, a ceiling lift system extending into the bathroom was put in place for use in all EMU patients when out of bed. In the subsequent 15 months, there have been zero falls. The results reinforce both the need for diligent safety standards to prevent falls in the EMU as well as the challenges in identifying the most effective practices to achieve this goal.