Allopurinol improves cardiac dysfunction after ischemia-reperfusion via reduction of oxidative stress in isolated perfused rat hearts.
It has been reported that the xanthine oxidase inhibitor, allopurinol, has a protective effect on ischemia - reperfusion injury, but the precise mechanism of its action is still unclear. Therefore, in the present study the mechanisms of the myocardial protection of allopurinol were evaluated in isolated perfused rat hearts. Allopurinol significantly inhibited myocardial xanthine oxidase activity, and improved left ventricular dysfunction after ischemia - reperfusion. In addition, the lactate dehydrogenase content in the coronary effluent obtained after reperfusion was significantly decreased. ATP, ADP, AMP and IMP significantly decreased, whereas inosine, hypoxanthine and xanthine significantly increased after ischemia in both the control and allopurinol groups. The concentration of xanthine was significantly decreased after ischemia - reperfusion in the allopurinol group; however, allopurinol did not affect the other purine metabolites. To evaluate the accumulation of oxidative stress, thiobarbituric acid reactive substances (TBARS) production in myocardial tissue was measured and allopurinol significantly decreased TBARS formation after ischemia - reperfusion. Finally, myocardial hydroxyl radicals were directly measured by electron spin resonance spectroscopy with the nitroxide radical 4-hydroxy-2, 2,6,6-tetramethyl-piperidine-N-oxyl. Hydroxyl radicals significantly increased immediately after reperfusion, but were significantly decreased in the allopurinol group. In conclusion, allopurinol reduced myocardial injury after ischemia-reperfusion by suppressing oxidative stress, but not by salvage of ATP. These findings may lead to the development of new therapeutic strategies for myocardial ischemia - reperfusion injury.


Mycobacterium abscessus Displays Fitness for Fomite Transmission.
Mycobacterium abscessus is a rapidly growing nontuberculous mycobacterium (NTM) increasingly reported in soft tissue infections and chronic lung diseases, including cystic fibrosis. The environmental source of M. abscessus has not been definitively identified, but NTM have been detected in soil and water. To determine the potential of soil-derived M. abscessus as an infectious source, we explored the association, growth, and survival of M. abscessus with defined mineral particulates, including kaolin, halloysite, and silicone dioxide, and house dust as possible M. abscessus fomites. M. abscessus physically associated with particulates, and the growth of M. abscessus was enhanced in the presence of both kaolin and house dust. M. abscessus survived desiccation for 2 weeks but was not viable after 3 weeks. The rate of decline of M. abscessus viability during desiccation was reduced in the presence of house dust. The evidence for enhanced growth and survival of M. abscessus during alternating growth and drying periods suggests that dissemination could occur when in wet or dry environments. These studies are important to understand environmental survival and acquisition of NTM.IMPORTANCE The environmental source of pulmonary Mycobacterium abscessus infections is not known. Fomites are nonliving carriers of infectious agents and may contribute to acquisition of M. abscessus This study provides evidence that M. abscessus growth is enhanced in the presence of particulates, using kaolin, an abundant natural clay mineral, and house dust as experimental fomites. Moreover, M. abscessus survived desiccation for up to 2 weeks in the presence of house dust, kaolin, and several chemically defined mineral particulates; mycobacterial viability during extended periods of dessication was enhanced by the presence of house dust. The growth characteristics of M. abscessus with particulates suggest that a fomite mechanism of transmission may contribute to M. abscessus acquisition, which may lead to strategies to better control infections by M. abscessus and related organisms.


Treatment of idiopathic membranous nephropathy.
Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.


NIH toolbox for assessment of neurological and behavioral function.
At present, there are many studies that collect information on aspects of neurologic and behavioral function (cognition, sensation, movement, emotion), but with little uniformity among the measures used to capture these constructs. Further, available measures are generally expensive, normed on homogenous nondiverse populations, not easily administered, do not cover the lifespan (or have easily linked pediatric and adult counterparts for the purposes of longitudinal comparison), and not based on the current thinking in the neuroscience community. There is also a paucity of measurement tools to gauge normal children in the motor and sensation domain areas, and many of these measures rely heavily on proxy reporting. Investigators have expressed the need for brief assessment tools that could address these issues and be used as a form of "common currency" across diverse study designs and populations. This ability to assess functionality along a common metric and "crosswalk" across measures is essential to the process of being able to pool data, which is often necessary when a large and diverse sample is needed. When individual studies employ unique assessment batteries, comparisons between studies and combining data from multiple studies can be problematic. The contract for the NIH Toolbox for the Assessment of Neurological and Behavioral Function (www.nihtoolbox.org) was initiated by the NIH Blueprint for Neuroscience Research (www.neuroscienceblueprint.nih.gov) to develop a set of state-of-the-art measurement tools to enhance collection of data in large cohort studies and to advance the biomedical research enterprise.


Unidentified patients in the emergency department: a historical cohort study.
To characterize unidentified patients presenting to a single, urban emergency department (ED) in Canada. We report their demographics, ED course, post-ED discharge outcomes, and mode of identification. We performed a retrospective chart review using descriptive analyses to assess unidentified patients admitted to Royal University Hospital and St. Paul's Hospital EDs between May 1, 2018, and April 30, 2019, in Saskatoon, Saskatchewan, Canada. We assessed demographic data, clinical presentation, mode of identification, discharge information, and major clinical outcomes. Unidentified patients were disproportionately male (64.9%), and mostly presented as Canadian Triage and Acuity Scale (CTAS) 1 (41.6%) and CTAS 2 (44.2%). Most patients arrived via emergency medical services (80.7%). The most common presenting complaints were substance misuse (33.3%) and trauma (24.6%). The average ED length of stay was 8.7 h (SD 18.6). Many patients received an inpatient consult (58.8%), and 22.3% received support services (e.g., social work). The 30-day mortality of all patients was 13.2%. Of those patients who survived to ED discharge, common dispositions included: home (36.0%), police services (3.5%), or emergency shelters (3.5%). Four (3.5%) patients returned to the hospital unidentified within the study period, and 6.7% of patients discharged from the ED returned within 48 hours. Unidentified patients are a high-needs demographic that present mostly with substance misuse or trauma. Repeat ED attendance, sometimes as unidentified patients again, calls for initiatives that facilitate prompt identification, better discharge planning, and linkage to social supports.


Mandatory Vision Test for Driver License Renewal in Association With Traffic Fatality and Injury Among Older Road Users in Utah.
In 2011, Utah began requiring that drivers aged 65 years and older pass a vision test at each license renewal. This study aims to investigate if the mandatory vision test associated with motor vehicle fatality and injury rates in older road users. We fit controlled interrupted time series analysis models to compare fatality and injury rates for older adults (65+) affected by the law to younger adults (45-64) unaffected by the law. The models yielded estimates of differential level and slope changes in fatality and injury rates, which we used to estimate policy associations. We did not find evidence that implementing an accelerated vision test for older adults in Utah was associated with a reduction in injury or fatality rates among older (65+) drivers and non-drivers relative to those aged 45-64. Other strategies might be considered to prevent fatal MVCs in older adults.


Cancer incidence among semiconductor and electronic storage device workers.
To evaluate cancer incidence among workers at two facilities in the USA that made semiconductors and electronic storage devices. 89 054 men and women employed by International Business Machines (IBM) were included in the study. We compared employees' incidence rates with general population rates and examined incidence patterns by facility, duration of employment, time since first employment, manufacturing era, potential for exposure to workplace environments other than offices and work activity. For employees at the semiconductor manufacturing facility, the standardised incidence ratio (SIR) for all cancers combined was 81 (1541 observed cases, 95% confidence interval (CI) 77 to 85) and for those at the storage device manufacturing facility the SIR was 87 (1319 observed cases, 95% CI 82 to 92). The subgroups of employees with > or =15 years since hiring and > or =5 years worked had 6-16% fewer total incidents than expected. SIRs were increased for several cancers in certain employee subgroups, but analyses of incidence patterns by potential exposure and by years spent and time since starting in specific work activities did not clearly indicate that the excesses were due to occupational exposure. This study did not provide strong or consistent evidence of causal associations with employment factors. Data on employees with long potential induction time and many years worked were limited. Further follow-up will allow a more informative analysis of cancer incidence that might be plausibly related to workplace exposures in the cohort.


Nicotine enhances the locomotor stimulating but not the conditioned rewarding effect of ethanol in DBA/2J mice.
One hypothesis to explain the high rate of nicotine and alcohol (ethanol [EtOH]) co-abuse is that these drugs have enhanced rewarding effects when taken together. The goal of this work was to use the conditioned place preference (CPP) procedure to determine whether nicotine would enhance the development of EtOH-induced CPP. The conditioned rewarding effects of nicotine (1 or 2 mg/kg of nicotine tartrate), EtOH (1 g/kg), and nicotine plus EtOH in combination were assessed using a well-established CPP procedure chosen specifically for examining alterations in the development of EtOH-induced CPP by nicotine. In addition, the reference dose procedure was used to directly compare the conditioned rewarding effect of EtOH versus nicotine plus EtOH. DBA/2J mice were used because they are an inbred strain that has repeatedly been shown to develop CPP to EtOH. Neither dose of nicotine alone produced CPP, whereas EtOH did, using the standard EtOH CPP procedure. The magnitude of EtOH-induced CPP was not affected by co-administration of 1 mg/kg nicotine, but 2 mg/kg nicotine interfered with the development of EtOH-induced CPP. Using the reference dose procedure, there was no significant preference or aversion for either nicotine + EtOH dose combination versus EtOH alone. However, combined nicotine and EtOH had a larger effect on locomotor activity, during the conditioning trials, compared to their additive effect when given alone, consistent with previous data. These data do not support the hypothesis that nicotine enhances the conditioned rewarding effect of EtOH. This finding differs from the combined locomotor stimulant effects of nicotine and EtOH that were observed in this study and in our previously published work, and suggests that combined stimulant effects of nicotine and EtOH do not predict enhanced reward.


Collaborative Care on the Stroke Unit: A Cross-Sectional Outcomes Study.
The aim of this study was to evaluate the economic and quality outcomes associated with a collaborative advanced practice nurse and hospitalist physician model of care on the inpatient stroke unit as compared with usual hospitalist physician-led care. High functioning collaborative teams are anticipated to be essential under value-based reimbursement. Hospitalist nurse practitioners were assigned to the stroke unit in collaboration with hospitalist physicians to implement daily hospital management for patients with stroke and transient ischemic attack. To evaluate outcomes associated with the care model, a retrospective cross-sectional design was used with 100 patients in the collaborative advanced practice nurse and hospitalist physician care group and 100 patients in the usual hospitalist physician-led care group. Primary outcome measures were length of stay, 30-day readmissions, stroke core measure documentation, and patient experiences of care. Analysis of demographic characteristics assured that the samples were similar. The collaborative care group performed better on one of five stroke core quality measures and on two of three patient experiences of care measures. Mean length of stay and hospital readmissions were similar between groups. Five patients left the stroke unit against medical advice in the usual hospitalist physician-led care group, whereas there were no discharges against medical advice in the collaborative care group. Advanced practice nurse and hospitalist physician collaboration is a promising model for healthcare quality improvement during inpatient stroke care; results are likely generalizable to other adult medicine populations.


Unraveling Transformative Effects after tDCS and BCI Intervention in Chronic Post-Stroke Patient Rehabilitation-An Alternative Treatment Design Study.
Stroke is a debilitating clinical condition resulting from a brain infarction or hemorrhage that poses significant challenges for motor function restoration. Previous studies have shown the potential of applying transcranial direct current stimulation (tDCS) to improve neuroplasticity in patients with neurological diseases or disorders. By modulating the cortical excitability, tDCS can enhance the effects of conventional therapies. While upper-limb recovery has been extensively studied, research on lower limbs is still limited, despite their important role in locomotion, independence, and good quality of life. As the life and social costs due to neuromuscular disability are significant, the relatively low cost, safety, and portability of tDCS devices, combined with low-cost robotic systems, can optimize therapy and reduce rehabilitation costs, increasing access to cutting-edge technologies for neuromuscular rehabilitation. This study explores a novel approach by utilizing the following processes in sequence: tDCS, a motor imagery (MI)-based brain-computer interface (BCI) with virtual reality (VR), and a motorized pedal end-effector. These are applied to enhance the brain plasticity and accelerate the motor recovery of post-stroke patients. The results are particularly relevant for post-stroke patients with severe lower-limb impairments, as the system proposed here provides motor training in a real-time closed-loop design, promoting cortical excitability around the foot area (Cz) while the patient directly commands with his/her brain signals the motorized pedal. This strategy has the potential to significantly improve rehabilitation outcomes. The study design follows an alternating treatment design (ATD), which involves a double-blind approach to measure improvements in both physical function and brain activity in post-stroke patients. The results indicate positive trends in the motor function, coordination, and speed of the affected limb, as well as sensory improvements. The analysis of event-related desynchronization (ERD) from EEG signals reveals significant modulations in Mu, low beta, and high beta rhythms. Although this study does not provide conclusive evidence for the superiority of adjuvant mental practice training over conventional therapy alone, it highlights the need for larger-scale investigations.


Morphological changes in neutron irradiated red blood cells.
Living human red blood cells (erythrocytes) were irradiated with a beam of thermal neutrons having a thermal neutron flux of 9.4 X 10(9) neutrons/cm2 per sec corresponding to a dose rate of 5 Gray per hour. The neutron beam was obtained from the thermal neutron facility at the MIT Nuclear Reactor and contained some gamma-ray contamination which contributes approximately 8% of the dose effect. Approximately 92% of the dose effect is due to the neutron radiation. Populations of neutron irradiated red blood cells were examined under scanning electron microscopy to observe morphological changes due to the radiation dose. The thermal neutron doses ranged from zero for controls to 75 Gray, and cell populations were examined at various post-irradiation time periods of 10, 48, and 96 h. A four-stage discoid to spheroid shape transformation of the damaged red blood cells was characterized, and the time dependence of each transformation stage was determined for both unirradiated and irradiated cells. The radiation dose caused an initial dose-dependent shift from Stage 1 to Stage 2 with an associated increase in the transformation rate constants. The thermal neutron doses delivered are considered to be in the low dose range for radiation effects on red blood cells, yet the pronounced effects indicate a high relative biological effectiveness (RBE) for thermal neutrons.


Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
Tumor vasculature is known to be more permeable than the vasculature found in healthy tissue, which in turn can lead to a more aggressive tumor phenotype and impair drug delivery into tumors. While the stiffening of the stroma surrounding solid tumors has been reported to increase vascular permeability, the mechanism of this process remains unclear. Here, we utilize an in vitro model of tumor stiffening, ex ovo culture, and a mouse model to investigate the molecular mechanism by which matrix stiffening alters endothelial barrier function. Our data indicate that the increased endothelial permeability caused by heightened matrix stiffness can be prevented by pharmaceutical inhibition of focal adhesion kinase (FAK) both in vitro and ex ovo. Matrix stiffness-mediated FAK activation determines Src localization to cell-cell junctions, which then induces increased vascular endothelial cadherin phosphorylation both in vitro and in vivo. Endothelial cells in stiff tumors have more activated Src and higher levels of phosphorylated vascular endothelial cadherin at adherens junctions compared to endothelial cells in more compliant tumors. Altogether, our data indicate that matrix stiffness regulates endothelial barrier integrity through FAK activity, providing one mechanism by which extracellular matrix stiffness regulates endothelial barrier function. Additionally, our work also provides further evidence that FAK is a promising potential target for cancer therapy because FAK plays a critical role in the regulation of endothelial barrier integrity.-Wang, W., Lollis, E. M., Bordeleau, F., Reinhart-King, C. A. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.


Biochemical evidence for the presence of an actin protein in Tetrahymena pyriformis.
A protein from an ATP extract prepared from an acetone powder of Tetrahymena pyriformis GL was identified as actin. The protein migrated slightly behind muscle actin on sodium dodecyl sulphate (SDS)/10% polyacrylamide gels (SDS/PAGE) with an apparent molecular weight of 47 500 (47.5 X 10(3) Mr). Partial proteolysis of this band with Staphylococcus aureus V-8 protease followed by electrophoresis revealed a pattern of peptides in which at least four peptides were similar to those observed after digestion of rabbit skeletal muscle actin. The 47.5 X 10(3) Mr protein appeared particularly susceptible to endogenous proteolytic cleavage, which was inhibited by leupeptin. An ATP extract prepared with leupeptin was applied to a DNase I-affinity column and a distinct peak was eluted with 3 M-guanidine . HCl; the DNase I-binding protein appeared as a distinct band on SDS/PAGE with an apparent molecular weight of 47.5 X 10(3) Mr. In the absence of leupeptin, the DNase I-binding protein appeared as a broad 34 X 10(3) Mr band on gels. Both the ATP extract and the DNase I-binding protein showed reactivity with commercially available antiserum raised against native chicken skeletal muscle actin as determined by an enzyme-linked immunosorbance assay (ELISA). Immuno-blotting studies and affinity purification of this antiserum showed that the recognition was not specific to the 47.5 X 10(3) Mr protein. However, using affinity-purified anti-actin antibodies raised against denatured actin from chick smooth muscle, recognition of the 47.5 X 10(3) Mr protein and a 34 X 10(3) Mr protein was shown. In negatively stained preparations from an ATP extract after two cycles of polymerization and depolymerization there were filaments, 8-12 nm diameter, which did not decorate with subfragment S-1 of myosin, but which resembled intermediate filaments. Analysis of these filaments on SDS/PAGE indicated an intensely stained 54 X 10(3) Mr band. It is suggested that, in vitro, Tetrahymena intermediate filaments assemble under conditions expected to assemble actin filaments. Thus, in Tetrahymena there is a protein that resembles actin in its extractability, molecular weight, peptide pattern after partial proteolysis, DNase I-binding capacity and reactivity with anti-actin antibodies. However, this protein did not assemble into actin filaments in crude extracts.


Relation of study quality, concordance, take home message, funding, and impact in studies of influenza vaccines: systematic review.
To explore the relation between study concordance, take home message, funding, and dissemination of comparative studies assessing the effects of influenza vaccines. Systematic review without meta-analysis. Search of the Cochrane Library, PubMed, Embase, and the web, without language restriction, for any studies comparing the effects of influenza vaccines against placebo or no intervention. Abstraction and assessment of quality of methods were carried out. We identified 259 primary studies (274 datasets). Higher quality studies were significantly more likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% confidence interval 4.24 to 63.04) and less likely to favour effectiveness of vaccines (0.04, 0.02 to 0.09). Government funded studies were less likely to have conclusions favouring the vaccines (0.45, 0.26 to 0.90). A higher mean journal impact factor was associated with complete or partial industry funding compared with government or private funding and no funding (differences between means 5.04). Study size was not associated with concordance, content of take home message, funding, and study quality. Higher citation index factor was associated with partial or complete industry funding. This was sensitive to the exclusion from the analysis of studies with undeclared funding. Publication in prestigious journals is associated with partial or total industry funding, and this association is not explained by study quality or size.


[Pelvic presentation].
Labour is very important in breech presentation and it is associated to significant morbidity and mortality enhancement in recent years. The authors made a retrospective study of breech presentation and labour with this kind of fetal presentation, in Santa Maria Hospital in 1993 and analysed the following data: maternal age, parity, gestational age, the mode of delivery, the fetal weight, the maternal and fetal morbidity and mortality. The authors also reviewed the Literature on the incidence, the most frequent complications and the management in labour to compare with the results of the study. The authors found that the incidence of breech presentation in this hospital is slightly higher (4.7%) than the universal data. The remaining results had no significant difference.


Blood pressure in adolescence, adipokines and inflammation in young adults. The rio de janeiro study.
The impact of blood pressure (BP) during adolescence on other cardiovascular risk factors in young adults is important for the primary prevention. To evaluate BP, anthropometric indexes, metabolic and inflammatory profiles in young individuals stratified by their BP behavior recorded for 18 years. A total of 116 individuals, of whom 63 were males, from the Rio de Janeiro study (follow-up of 17.76 ± 1.63 years), were assessed at two moments: A1 (12.40 ± 1.49 years) and A2 (30.09 ± 2.01 years). The 116 individuals were divided into two groups: GN (n = 71), of participants with normal BP at A1; and GH (n = 45), of those with abnormal BP at A1. BP, weight, height and body mass index (BMI) were measured at A1 and A2. At A2, abdominal circumference (AC) and laboratory, metabolic and inflammatory variables were included. 1) No difference was observed between the groups as regards age and gender; 2) At A2, GH showed higher mean weight, BMI, BP, insulin, HOMA-IR (p < 0.001), leptin (p < 0.02), apolipoprotein B100 and A1 (p < 0.02), apolipoprotein B100 / apolipoprotein A1 ratio (p < 0.010); and higher prevalences of overweight/obesity (p < 0.001), of increased AC (p < 0.001) and of hypertension (p < 0.02); 3) No difference was observed between the groups as regards the inflammatory variables; 4) There was a positive correlation of BP at A1 with BP, BMI, insulin, leptin and HOMA-IR at A2 (p < 0.05). BP in adolescence was associated with higher values of BP, and anthropometric and metabolic variables in young adulthood, but not with inflammatory variables.


Expression of the affected A gamma globin gene associated with Greek nondeletion hereditary persistence of fetal hemoglobin.
The overexpressed A gamma globin gene in the Greek type of nondeletion hereditary persistence of fetal hemoglobin has a unique single-base substitution located at position -117 relative to the site of transcription initiation. This gene and its normal counterpart were transferred into cultured cell lines by using a retroviral vector. The only difference in expression between the transferred normal and mutant gamma genes was observed in the human erythroleukemia cell line KMOE after exposure of the cells to cytosine arabinoside, a condition that resulted in an adult pattern of endogenous globin gene expression by the cells and was associated with increased expression of the mutant gene.


Hyaluronan in intestinal homeostasis and inflammation: implications for fibrosis.
The causes of fibrosis, or the inappropriate wound healing, that follows chronic intestinal inflammation are not well defined and likely involve the contributions of multiple cellular mechanisms. As other articles in this series confirm, inflammatory cytokines clearly play a role in driving cell differentiation to the myofibroblast phenotype, promoting proliferation and extracellular matrix deposition that are characteristic of fibrotic tissue. However, controlling the balance of cytokines produced and process of myofibroblast differentiation appears to be more complex. This review considers ways in which hyaluronan, an extracellular matrix component that is remodeled during the progression of colitis, may provide indirect as well as direct cues that influence the balancing act of intestinal wound healing.


Long-term fate of the aneurysmal sac after endoluminal exclusion of abdominal aortic aneurysms.
Shrinkage of an abdominal aortic aneurysm (AAA) is the hallmark of successful endoluminal treatment. Our goal was to prospectively assess the midterm to long-term shrinkage of the AAA sac after endovascular repair. A total of 123 patients with AAA underwent endoluminal treatment with the Ancure device at our institution between February 1996 and February 2000. At least a 1-year follow-up was available for 70 of the 123 patients. AAA sac size, presence of endoleaks, calcifications, and outcome data were collected on these patients at 6, 12, 24, and 36 months after repair and compared with the preoperative AAA size and characteristics. All endoleaks found at the 6-month follow-up visit were treated aggressively with embolotherapy. An AAA sac regression of 0.5 cm or more was considered the minimum measurable decrease. Regression of the sac diameter to 3.5 cm or less was considered a complete collapse of the sac. Successful endoluminal repair was accomplished in 119 of 123 patients. The mortality rate was 0.8% (1/123). There was a steady decrease in AAA sac size from baseline (5.56 +/- 0.1 cm), to 6 months (5.0 +/- 0.14 cm, P =.0006), to 12 months (4.65 +/- 0.13 cm, P =.04), and to 24 months (4.26 +/- 0.16 cm, P =.03). At 24 months, 74% (29/39) had a decrease in sac size of 0.5 cm or more, with 28% (11/39) complete collapse. Patients with initial endoleaks had the same likelihood of regression of sac size (> or = 0.5 cm) when compared with the group of patients with no endoleaks at the 24-month evaluation (64% vs 76%, P =.09). Endoluminal AAA repair resulted in a significant reduction in sac size that continues up to 2 years. Significant shrinkage occurs as early as 6 months after placement. The initial presence of endoleaks does not predict the lack of sac regression.


Towards understanding the phosphorylation code of tau.
We describe our efforts to combine in vitro enzymatic reactions with recombinant kinases to phosphorylate the neuronal tau protein, and NMR spectroscopy to unravel the resulting phosphorylation pattern in both qualitative and quantitative manners. This approach, followed by functional assays with the same samples, gives access to the complex phosphorylation code of tau. As a result, we propose a novel hypothesis for the link between tau (hyper)phosphorylation and aggregation.


International variation in proximal femur bone mineral density.
We observed higher proximal femur bone mineral density (BMD) in European women compared to average values derived from US Caucasian women in the National Health and Nutrition Examination Survey (NHANES) study. Across European centres, Parisian women had lower proximal femur BMD compared to women from Kiel or Sheffield. Proximal femur BMD of US adults (NHANES III) may not accurately reflect that of European women. We examined the heterogeneity of BMD across European and US Caucasian women and across different European populations. Proximal femur BMD was measured in women ages 20-39 years (n=258) and 55-79 years (n=1,426) from three European centres. Cross-calibrated BMD for total hip, femoral neck, trochanter and intertrochanter were examined. International variation in BMD was assessed by comparing means and SDs in the European data with those from the US NHANES III study. European populations were stratified into 5-year age bands to establish individual centre reference intervals. Between-centre differences were assessed using ANOVA and post hoc Fisher's least significant difference tests. European women had higher BMD than US women: The differences were 7.1% to 14.2% (p<0.001) and 0% to 3.9% (p<0.05) in the older and younger women, respectively. Standard deviations for BMD at the different sites were comparable to those for US women. Among older, but not younger European women, proximal femur BMD was significantly lower in French women (Paris) than in women from Germany (Kiel) or the UK (Sheffield) (difference=5.0% to 9.6%, p<0.05). International variation in hip BMD does exist, with international and between-centre differences being less evident at the femoral neck.


[The significance of associated malformations of the central nervous system in myelomeningocele].
Neural tube defects are the most frequent congenital structural malformations in Norway. Approximately half of these are myelomeningocele. Infants with myelomeningocele frequently have hydrocephalus at birth. Problems with intracranial pressure may as well develop later. There are several reports on pathological corpus callosum and an increasing number of reports on cognitive problems in patients with myelomeningocele. Most patients with myelomeningocele have a tethered spinal cord, and some have syringomyelia. Chiari malformation type II is a malformation of the skull and brainstem which is frequently observed in individuals with myelomeningocele. Chiari malformation may cause severe respiratory problems in infants. Chiari malformation, tethered cord as well as syringomyelia are associated with a range of neurological problems which may progress in adulthood. Surgical intervention may improve the situation. Anaesthesia may induce neurological complications in individuals with Chiari malformation or syringomyelia. Since pregnancy and childbirth are associated with complications, women with myelomeningocele should be examined before they become pregnant. Children and adults with myelomeningocele should routinely undergo MRI examinations of caput and the spinal cord to clarify their anatomical situation.


Evidence for the formation of multimeric forms of the 5A11/HT7 antigen.
The 5A11 antigen is the avian homologue of a developmentally regulated 45-kDa glycoprotein of the immunoglobulin super-gene family implicated in heterotypic cell-to-cell interactions. Employing chemical cross-linking agents, we provide evidence for oligomerization of the 5A11 antigen in Triton X-100-solubilized preparations of neural retina, liver, and erythrocytes and in intact erythrocytes. Dimerization was demonstrated through partial proteolytic digestion and diagonal gel electrophoresis. Sedimentation velocity separation demonstrated that the 5A11 dimer, derived from retina, is part of a larger macromolecular complex characterized by a sedimentation rate comparable to that of the glutamine synthetase octomer (S = 15.2). In contrast, the sedimentation velocities of the dimer and monomer from erythrocytes were similar. These data provide the first biochemical evidence of interaction of the 5A11 antigen and differences in these interactions between tissues.


Configuration of the action observation network depends on the goals of the observer.
Observing the actions of others engages a core action observation network (AON) that includes the bilateral inferior frontal cortex (IFC), posterior superior temporal sulcus (pSTS) and inferior parietal lobule (IPL) (Caspers et al., 2010). Each region in the AON has functional properties that are heterogeneous and include representing the perceptual properties of action, predicting action outcomes and making inferences as to the goals of the actor. Critically, recent evidence shows that neural representations within the pSTS are sharpened when attending to the kinematics of the actor, such that the top-down guided attention reshapes underlying neural representations. In this study we evaluate how attention alters network connectivity within the AON as a system. Cues directed participant's attention to the goal, kinematics, or identity depicted in short action animations while brain responses were measured by fMRI. We identified those parcels within the AON with functional connectivity modulated by task. Results show that connectivity between the right pSTS and right IFC, and bilateral extended STS (STS+) were modulated during action observation such that connections were strengthened when the participant was attending to the action than goal. This finding is contrasted by the univariate results, which no univariate modulations in these brain regions except for right IFC. Using the functional networks defined by Yeo et al. (2011), we identified the parcels that are modulated by the attention to consist mainly of the fronto-parietal control network and default mode networks. These results are consistent with models of top-down feedback from executive system in the IFC to pSTS and implicates a right lateralized dual pathway model for action observation when focused on whole-body kinematics.


Beyond fixation durations: Recurrence quantification analysis reveals spatiotemporal dynamics of infant visual scanning.
Standard looking-duration measures in eye-tracking data provide only general quantitative indices, while details of the spatiotemporal structuring of fixation sequences are lost. To overcome this, various tools have been developed to measure the dynamics of fixations. However, these analyses are only useful when stimuli have high perceptual similarity and they require the previous definition of areas of interest (AOIs). Although these methods have been widely applied in adult studies, relatively little is known about the temporal structuring of infant gaze-foraging behaviors such as variability of scanning over time or individual scanning patterns. Thus, to shed more light on the spatiotemporal characteristics of infant fixation sequences we apply for the first time a new methodology for nonlinear time-series analysis-the recurrence quantification analysis (RQA). We present how the dynamics of infant scanning varies depending on the scene content during a "pop-out" search task. Moreover, we show how the normalization of RQA measures with average fixation durations provides a more detailed account of the dynamics of fixation sequences. Finally, we link the RQA measures of temporal dynamics of scanning with the spatial information about the stimuli using heat maps of recurrences without the need for defining a priori AOIs and present how infants' foraging strategies are driven by the image content. We conclude from our findings that the RQA methodology has potential applications in the analysis of the temporal dynamics of infant visual foraging offering advantages over existing methods.


Conventional (continuous) EEG monitoring in the NICU.
Conventional EEG is being used more frequently in NICUs in the U.S. with the advent of therapeutic hypothermia and the growth of neurocritical care intensivists & units. Historical applications have included assessing encephalopathy, seizure evaluation and prognosis. Past reluctance or limitation of the use in the NICU are receding with the digitization of EEG recordings and increasing interest in the neonatal brain. Continuous EEG monitoring is expanding the potential for its application as a brain monitoring tool to stratify initial injury severity, monitor seizure response to treatment, and detect sentinel neurologic events in the NICU, in addition to guiding neurotherapeutic options. The progression of the EEG background after an acute insult can also increase its prognostic specificity and provide another immediate marker of NICU neurologic outcome. The future of EEG monitoring in the NICU holds many possibilities and may greatly advance the new field of neuroprotection in the NICU.


Interacting effects of vessel noise and shallow river depth elevate metabolic stress in Ganges river dolphins.
In riverine 'soundscapes', complex interactions between sound, substrate type, and depth create difficulties in assessing impacts of anthropogenic noise pollution on freshwater fauna. Underwater noise from vessels can negatively affect endangered Ganges river dolphins (Platanista gangetica), which are 'almost blind' and rely entirely on high-frequency echolocation clicks to sense their environment. We conducted field-based acoustic recordings and modelling to assess acoustic responses of Platanista to underwater noise exposure from vessels in the Ganga River (India), which is now being transformed into a major waterway. Dolphins showed enhanced activity during acute noise exposure and suppressed activity during chronic exposure. Increase in ambient noise levels altered dolphin acoustic responses, strongly masked echolocation clicks, and more than doubled metabolic stress. Noise impacts were further aggravated during dry-season river depth reduction. Maintaining ecological flows, downscaling of vessel traffic, and propeller modifications to reduce cavitation noise, could help mitigate noise impacts on Ganges river dolphins.


Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis.
FoxP3(+)CD4(+)CD25(+) regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed.


Clinicopathological features and prognosis assessment of extranodal follicular dendritic cell sarcoma.
To establish a model for prognosis assessment of extranodal follicular dendritic cell (FDC) sarcoma. Nine lesions were examined by routine and molecular approaches. Clinicopathological factors from the new cases and 97 reported cases were analyzed for their prognostic values. The current lesions were found in five male and four female patients, located mainly in the head and neck area and averaging 7.2 cm in size. Six patients had recurrence or metastasis and three remained free of disease. The 106 patients (male/female ratio, 1.1:1) were aged from 9 to 82 years (median, 44 years). The tumor sizes ranged from 1.5 to 21 cm (mean, 7.4 cm). Abdominal/pelvic region was affected most frequently (43%). Surgical resection was performed in 100 patients, followed by radiation and/or chemotherapy in 35 of them. Follow-up data were available in 91 cases, covering a period of 3-324 mo (mean, 27 mo; median, 19 mo). Of the informative cases, 38 (42%) had recurrence or metastasis, and 12 (13%) died of the disease. These tumors were classified histologically into low- and high-grade lesions. A size > or = 5 cm (P = 0.003), high-grade histology (P = 0.046) and a mitotic count > or = 5/10 HPF (P = 0.013) were associated with tumor recurrence. The lesions were defined as low-, intermediate- and high-risk tumors, and their recurrence rates were 16%, 46% and 73%, and their mortality rates 0%, 4% and 45%, respectively. Extranodal FDC tumors behave like soft tissue sarcomas. Their clinical outcomes are variable and can be evaluated according to their sizes and grades.


[Application of bolt-like post crown system in restoration of molar residual root and crown with low occlusogingival distance].
To evaluate the clinical effects of bolt-like post crown system in restoration of molar residual root and crown with low occlusogingival distance and large root bifurcation angle. Thirty two molar residual roots and crowns from 25 patients with low occlusogingival distance (<4 mm) and large root bifurcation angle were involved in this study. First, the root canals were prepared according to their natural directions following the standard procedures. Accurate impressions were taken with silicone. The core crown and the post which would inserted the straight root canal were founded together,and the blot-like post which would inserted the root canal with bigger bifurcat were founded alone. Finally, the two parts were cemented together in patient after try-in with RelyX™ Unicem cement. Except 3 patients who were lost during the follow up period, the remaining 22 patients (29 restorations) were followed up for 1 to 5 years. No prosthetic loosening or root fracture was observed during the follow-up period. All the fixed restorations were found with good marginal fitness, well masticatory function and favorable proximal contact relationship. Bolt-like post crown system is an ideal method for restoration of molar residual root and crown with low occlusogingival distance and large root bifurcation angle. This approach has positive effect on the retention, function and aesthetic outcome of the fixed restorations of molar residual root and crown with low occlusogingival distance.


LI-MLC: a label inference methodology for addressing high dimensionality in the label space for multilabel classification.
Multilabel classification (MLC) has generated considerable research interest in recent years, as a technique that can be applied to many real-world scenarios. To process them with binary or multiclass classifiers, methods for transforming multilabel data sets (MLDs) have been proposed, as well as adapted algorithms able to work with this type of data sets. However, until now, few studies have addressed the problem of how to deal with MLDs having a large number of labels. This characteristic can be defined as high dimensionality in the label space (output attributes), in contrast to the traditional high dimensionality problem, which is usually focused on the feature space (by means of feature selection) or sample space (by means of instance selection). The purpose of this paper is to analyze dimensionality in the label space in MLDs, and to present a transformation methodology based on the use of association rules to discover label dependencies. These dependencies are used to reduce the label space, to ease the work of any MLC algorithm, and to infer the deleted labels in a final postprocessing stage. The proposed process is validated in an extensive experimentation with several MLDs and classification algorithms, resulting in a statistically significant improvement of performance in some cases, as will be shown.


Diagnostic Accuracy of Cognitive Screening Instruments in Heart Failure: A Systematic Review.
Cognitive impairment is prevalent in heart failure (HF) with severe consequences, including increased risk of mortality and reduced ability to self-manage HF symptoms. Identifying cognitive impairment through screening would assist clinicians in managing HF and comorbid cognitive impairment. However, the accuracy of cognitive screening instruments for HF has not been adequately determined. The aim of this study was to determine the diagnostic accuracy of cognitive screening instruments in screening for mild cognitive impairment (MCI) in HF patients. A systematic review of major electronic bibliographic databases was searched from January 1999 to June 2013. Inclusion criteria were as follows: primary studies examining cognitive impairment in HF, administration of a cognitive screening instrument and neuropsychological test battery, and cognitive impairment indicated by performance on neuropsychological tests 1.5 SDs less than that of normative data. Methodological rigor of included publications was evaluated using 2 bias risk instruments: QUality Assessment of Diagnostic Accuracy Studies and STAndards for the Reporting of Diagnostic accuracy studies. The precision, accuracy, and receiver operating characteristic curves of the Mini Mental State Examination were computed. From 593 citations identified, 8 publications met inclusion criteria. Risk of bias included selective HF patient samples, and no study examined the diagnostic test accuracy of the cognitive screening instruments. The Mini Mental State Examination had low sensitivity (26%) and high specificity (95%) with a score of 28 or less as the optimal threshold for MCI screening. Screening for cognitive impairment in HF is recommended; however, future studies need to establish the diagnostic accuracy of screening instruments of MCI in this population.


The energetics of isomerisation in Keggin-series aluminate cations.
Electronic-structure calculations show that the ε-isomer of the polyoxoaluminate ion in the Keggin structure [AlO4-(Al(OH)2(H2O))12](7+) is the thermodynamically favoured one. Direct interconversion between the ε- and δ-isomers via cap rotation has a prohibitively high energy barrier in vacuo, suggesting that isomerisation in solution either proceeds via a dissolution-precipitation pathway, or that solvation and/or coordination to counterions reduces the barrier significantly. The implications for the formation of the [Al2O8Al28(OH)56(H2O)26](18+) ion are discussed.


Antiosteoporotic activity of the water extract of Dioscorea spongiosa.
After 60 MeOH and water extracts of natural crude drugs were screened for their ability to stimulate osteoblast proliferation, four MeOH extracts (Cynomorium songaricum, Drynaria fortunei, Lycium chinense, Rehmannia glutinosa) and seven water extracts (Cornus officinalis, Dendrobium nobile, Dioscorea spongiosa, Drynaria fortunei, Eucommia ulmoides, Lycium chinensis, Viscum coloratum) showed that potent activities were evaluated for inhibition of osteoclast formation. The results indicated that the water extract of D. spongiosa not only showed the strongest stimulation of osteoblast proliferation but also possessed potent inhibitory activity aganist osteoclast formation, whereas it showed lower cytotoxicity in osteoblast and bone marrow cells. A further in vivo experiment determined the antiosteoporotic activity of this extract, in which it inhibited the decrease in cancellous bone mineral content, cancellous bone mineral density, and cortical bone mineral content of the proximal tibia in ovariectomized rats.


Electronic, Crystal Chemistry, and Nonlinear Optical Property Relationships in the Dugganite A3B3CD2O14 Family.
A family of six nonlinear optical (NLO) materials, A3B3CD2O14 (A = Sr, Ba, or Pb; B = Mg or Zn; C = Te or W; and D = P or V), has been synthesized and characterized. In addition to the synthesis and crystal structures, comprehensive characterization of these compounds includes second harmonic generation (SHG) measurements, theoretical calculations, infrared and diffuse reflectance spectroscopies, and thermogravimetric measurements. We find that all of the reported materials are SHG-active at 1064 nm, with responses ranging from 2.8 to 13.5 × KDP, and exhibit absorption edges in the mid- to deep-ultraviolet regime. By systematically replacing the A, B, C, and D cations, we are able to tune these properties and investigate the role of different NLO-active structural units in producing the SHG responses. Specifically, our electronic structure calculations reveal that the presence of Pb(2+) on the A-site and Te(6+) on the C-site is critical for generating a large SHG response. The synthesis and structure-property relationships described in this family of materials will enable the design and discovery of new NLO materials.


Identification of neutrophil β2-integrin LFA-1 as a potential mechanistic biomarker in ANCA-associated vasculitis via microarray and validation analyses.
Leukocyte activation by anti-neutrophil cytoplasmic antibody (ANCA) and the subsequent leukocyte-endothelium interaction play a key role in the development of endothelial damage in ANCA-associated vasculitis (AAV). In contrast to that of leukocyte activation, the exact role of the leukocyte-endothelium interaction via integrin remains unclear. Here, we performed microarray and validation analyses to explore association between the expression levels of lymphocyte function-associated antigen-1 (LFA-1) and the clinical characteristics of patients with AAV. We performed gene set enrichment analysis (GSEA) to identify the functional gene sets differentially expressed between patients with AAV and other types of vasculitis and the healthy controls (HCs). Flow cytometry was performed to validate the GSEA results. Treatment-naïve patients were monitored until 24 weeks of treatment. To examine the role of LFA-1 in the neutrophil-endothelium interaction, we performed a leukocyte adhesion and transmigration assay using peripheral blood and human umbilical vein endothelial cells (HUVECs). GSEA revealed that the molecular pathways involving integrin-related genes were significantly upregulated in patients with AAV compared to that in patients with other types of vasculitis and the HCs. Flow cytometry revealed that the percentage of neutrophils expressing LFA-1 was significantly higher in patients with AAV than in those with large-vessel vasculitis or polyarteritis nodosa and the HCs. LFA-1 levels in the neutrophils were higher in patients with MPO-ANCA-positive expression than in those with a positive PR3-ANCA expression and correlated with the peripheral eosinophil count, serum rheumatoid factor titre, serum C-reactive protein levels, and the vasculitis activity score of systemic and chest components. After 24 weeks of treatment, including prednisolone, cyclophosphamide, rituximab, azathioprine, methotrexate, and/or tacrolimus, neutrophil LFA-1 expression remained high in the non-responder patients, but decreased in the responder patients. The in vitro assay showed that leukocyte migration toward HUVECs was dependent on the interaction between LFA-1 and intercellular adhesion molecule-1 (ICAM1); the migration of leukocytes was inhibited by blocking the adhesion of LFA-1 to ICAM1. The expression of LFA-1 in neutrophils is increased in patients with AAV. Neutrophil LFA-1 levels correlate with the clinical features of AAV. Inhibiting the adhesion of LFA-1 and ICAM1 impedes the neutrophil-endothelium interaction and may have a therapeutic role in AAV.


Splash Safety During Dermatologic Procedures Among US Dermatology Residents.
Dermatologists are at potential risk of acquiring infections from contamination of the mucous membranes by blood and body fluids. However, there are little data on splash safety during procedural dermatology. To determine dermatology resident perceptions about splash risk during dermatologic procedures and to quantify the rate of protective equipment use. An anonymous on-line survey was sent to 108 United States ACGME-approved dermatology residency programs assessing frequency of facial protection during dermatologic procedures, personal history of splash injury, and, if applicable, reasons for not always wearing facial protection. A total of 153 dermatology residents responded. Rates of facial protection varied by procedure, with the highest rates during surgery and the lowest during local anesthetic injection. Over 54% of respondents reported suffering facial splash while not wearing facial protection during a procedure. In contrast, 88.9% of respondents correctly answered that there is a small risk of acquiring infection from mucosal splash. Residency program recommendations for facial protection seem to vary by procedure. The authors' results demonstrate that although facial splash is a common injury, facial protection rates and protective recommendations vary significantly by procedure. These data support the recommendation for enhanced facial protection guidelines during procedural dermatology.


Machine learning to detect, stage and classify diseases and their symptoms based on inertial sensor data: a mapping review.
This article presents a systematic review aimed at mapping the literature published in the last decade on the use of machine learning (ML) for clinical decision-making through wearable inertial sensors. The review aims to analyze the trends, perspectives, strengths, and limitations of current literature in integrating ML and inertial measurements for clinical applications. The review process involved defining four research questions and applying four relevance assessment indicators to filter the search results, providing insights into the pathologies studied, technologies and setups used, data processing schemes, ML techniques applied, and their clinical impact. When combined with ML techniques, inertial measurement units (IMUs) have primarily been utilized to detect and classify diseases and their associated motor symptoms. They have also been used to monitor changes in movement patterns associated with the presence, severity, and progression of pathology across a diverse range of clinical conditions. ML models trained with IMU data have shown potential in improving patient care by objectively classifying and predicting motor symptoms, often with a minimally encumbering setup. The findings contribute to understanding the current state of ML integration with wearable inertial sensors in clinical practice and identify future research directions. Despite the widespread adoption of these technologies and techniques in clinical applications, there is still a need to translate them into routine clinical practice. This underscores the importance of fostering a closer collaboration between technological experts and professionals in the medical field.


[Monstrous, retroperitoneal liposarcoma--a case report].
Liposarcomas comprise about 20% of soft tissue sarcomas and occur in 14% in the retroperitoneal space originating in one third from the perirenal fat. The case of a patient with an extraordinary huge, resectable, well-differentiated retroperitoneal liposarcoma is reported. The presenting symptoms were abdominal pain and distension as well as weight gain. Magneticresonance imaging revealed a huge retroperitoneal tumor suspected of well-differentiated liposarcoma. Curative resection of the tumor could be obtained. Only 50% of all tumors are excised without residual tumor and recurrence, occurring in 90% after 10 years, is the main therapeutic challenge. Since neoadjuvant and adjuvant therapy as well as intraoperative radiotherapy failed to prove prognostic value, curative resection remains the main treatment for primary and recurrent liposarcomas.


Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells.
Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1β stimulation. Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. ILC3s stimulated with IL-23 plus IL-1β upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1β signaling pathway, as well as the IL-1β-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/β. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.


Wild-type microglia arrest pathology in a mouse model of Rett syndrome.
Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.


[Mechanism of the stimulating effect of protamines on the infectivity of DNA phages].
The interaction of styrin (protamine from sturgeon milt) with E. coli spheroplasts was investigated with the aid of the fluorescent probe--5-dimethylamino-1-naphthalenesulfonyl-chloride (DNS). Not less than 40% of the total (15 mug ml-1) DNA-protamine concentration was bound to spheroplasts. A part of the protein was found in the isolated membranes and inside the cell. There was a correlation between the binding of protein with spheroplasts and its biological action. The dansylation somehow decreased the protein stimulating activity in transfection.


A double blind randomised control trial investigating the efficacy of platelet rich plasma versus placebo for the treatment of greater trochanteric pain syndrome (the HIPPO trial): a protocol for a randomised clinical trial.
Greater trochanteric pain syndrome (GTPS) is a painful condition characterised by pain around the greater trochanter usually affecting middle-aged women. The majority of patients will improve with conservative management such as physiotherapy and non-steroidal anti-inflammatory drugs (NSAIDs); however, if this fails then more invasive treatments including corticosteroid injections and surgery may be required. Platelet-rich plasma (PRP) is an autologous blood product, which has a higher concentration of growth factors postulated to provide enhanced healing and anti-inflammatory properties. There have been numerous studies on PRP's efficacy in musculoskeletal soft tissue conditions with similar pathology to GTPS, with varying results, most promising being in plantar fasciopathy and patellar tendinopathy. Corticosteroids are the established second-line treatment, but do not always work long term. PRP may be a suitable alternative to corticosteroid in GTPS with longer-term effects; however, there are very limited reports. The Hip Injections PRP Vs Placebo (HIPPO) trial aims to assess the ability of PRP to improve symptoms and function in patients with GTPS. HIPPO is a single-centre, double-blind randomized placebo-controlled study in patients with a radiologically confirmed diagnosis of gluteus medius or minimus tendinopathy with swelling within the tendon insertion with or without bursitis. We aim to randomise 102 patients with GTPS to either the PRP or placebo (normal saline injection) treatment arm. Participants will receive one ultrasound (US) guided PRP/placebo injection into the trochanteric bursa and surrounding gluteus medius/minimus tendons. The primary outcome measure is the International Hip Outcome Tool-12. Secondary outcome measures will include a visual analogue score for pain, the three-level version of the EuroQol five-dimensional questionnaire and the modified Harris Hip Score. Outcomes will be measured at baseline, 3, 6 and 12 months. Participants will have the option at 6 months to have a repeat blinded injection or cross over to PRP. Analyses of primary and secondary outcomes will be made according to the intention-to-treat principle. The trial reporting will comply with Consolidated Standards of Reporting Trials (CONSORT) guidelines. The HIPPO study has been designed to test the hypothesis that PRP is effective in treating GTPS in patients who have failed conservative management and to assess the duration of effect of PRP. ClinicalTrials.gov, NCT03479190 . Registered on 27 March 2018.


Early changes in somatosensory function in spinal pain: protocol for a systematic review.
Back and neck pain are common conditions that have a high burden of disease. Changes in somatosensory function in the periphery, the spinal cord and the brain have been well documented at the time when these conditions have become chronic. It is unknown, however, how early these changes occur, what the timecourse is of sensory dysfunction and what the specific nature of these changes are in the first 12 weeks after onset of pain. In this paper, we describe the protocol for a systematic review of the literature on somatosensory dysfunction in the first 12 weeks after pain onset. We will conduct a comprehensive search for articles indexed in the databases Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and Cochrane Central Register of Controlled Trial (CENTRAL) from their inception to August 2013 that report on any aspect of somatosensory function in acute or subacute neck or back pain. Two independent reviewers will screen studies for eligibility, assess risk of bias and extract relevant data. Results will be tabulated and a narrative synthesis of the results conducted. Currently, there is a gap in our knowledge about the timing of somatosensory changes in back and neck pain. The systematic review outlined in this protocol aims to address this knowledge gap and inform developments in diagnostic tools and pain mechanism-based treatments. Our protocol has been registered on PROSPERO, CRD42013005113.


Extracorporeal photopheresis promotes IL-1β production.
Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP.


Psychometric properties of instrumented postural sway measures recorded in community settings in independent living older adults.
In the last few decades, research related to balance in older adults has been conducted in lab-based settings. The lack of portability and high cost that is associated with the current gold standard methods to quantify body balance limits their application to community settings such as independent living facilities. The purpose of the study was to examine the relative and absolute reliability and the convergent validity of static standing balance performance using an accelerometer device. A total of 131 participants (85% female, mean age 80 ± 8 years) were included for the validity aim, and a subsample of 38 participants were enrolled in the reliability testing (89% female, mean age 76 ± 7 years). The root-mean-square (RMS) and normalized path length (NPL) for sway in antero-posterior (AP) and medio-lateral (ML) directions were calculated for different standing balance conditions. Test-retest reliability was assessed over two testing visits occurring 1 week apart using the intraclass correlation coefficient (ICC) for relative reliability, and the minimal detectable change (MDC) was calculated for the absolute reliability. Spearman's rank correlation coefficient was used to test convergent validity at baseline between balance measurements and related mobility measures. Reliability of balance performance using accelerometers was good to excellent with ICC values ranging from 0.41 to 0.83 for RMS sway and from 0.49 to 0.82 for NPL sway. However, the ICC during semi-tandem stance in A-P direction was 0.35, indicating poor reliability. The MDC of the sway measurements ranged from 2.4 to 9.4 for the RMS and 5.2 to 13.8 for the NPL. Balance measurements were correlated with mobility measurements. Using a portable accelerometer to quantify static standing postural control provides reliable measurements in community settings.


PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.
The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.


Fully-Occluded Target Selection in Virtual Reality.
The presence of fully-occluded targets is common within virtual environments, ranging from a virtual object located behind a wall to a datapoint of interest hidden in a complex visualization. However, efficient input techniques for locating and selecting these targets are mostly underexplored in virtual reality (VR) systems. In this paper, we developed an initial set of seven techniques techniques for fully-occluded target selection in VR. We then evaluated their performance in a user study and derived a set of design implications for simple and more complex tasks from our results. Based on these insights, we refined the most promising techniques and conducted a second, more comprehensive user study. Our results show how factors, such as occlusion layers, target depths, object densities, and the estimation of target locations, can affect technique performance. Our findings from both studies and distilled recommendations can inform the design of future VR systems that offer selections for fully-occluded targets.


Amplified fragment length polymorphism reveals specific epigenetic distinctions between Mycobacterium avium subspecies paratuberculosis isolates of various isolation types.
Amplified fragment length polymorphism (AFLP) was employed as a genetic analysis tool for the study of the genetic relatedness of Mycobacterium avium subsp. paratuberculosis isolates harvested from bovine fecal samples and from bovine or human tissues. This analysis revealed genetic differences between these two isolate types that were confirmed through cluster analysis. Dendrogram analysis separated these two isolate types based on the isolation scheme (tissue-associated versus fecal M. avium subsp. paratuberculosis isolates). Further sequence analysis of unique genetic regions from each isolation type revealed no genetic sequence differences. However, Clustal DNA alignments identified AFLP restriction enzyme sites that were undigested in the tissue-associated isolates. AFLP analysis also disclosed that the same AFLP restriction sites were digested in all of the fecal isolates. Sequence analysis further revealed a consensus sequence upstream of the undigested restriction sites for possible methyltransferase recognition in the tissue-associated M. avium subsp. paratuberculosis isolates.


Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines.
A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 μg/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series.


Extracranial vertebral artery pseudoaneurysm presenting as subarachnoid hemorrhage.
True aneurysms of the extracranial vertebral artery are rare. The usual pathogenesis of aneurysms in this location is either penetrating or blunt trauma with resultant pseudoaneurysm formation. We report a postpartum patient with a presumed traumatic pseudoaneurysm of the extracranial vertebral artery presenting with subarachnoid hemorrhage. A 41-year-old woman had three episodes of neck stiffness 1 month after an uncomplicated vaginal delivery. The last episode, 3 days before admission, was accompanied by intense neck and head pain and paresthesias that extended into the left arm, thumb, and forefinger. Lumbar puncture showed subarachnoid hemorrhage. Angiography revealed a left vertebral artery dissection from C6-7 to C3 with pseudoaneurysm at C5-6. Computed tomography demonstrated impingement of the C6 root at the foramen by this lesion. The lesion was successfully treated by balloon occlusion of the vertebral artery. We present a patient with an extracranial vertebral pseudoaneurysm with subarachnoid hemorrhage and cervical root impingement. To our knowledge, this is the first case of such a lesion presenting as subarachnoid hemorrhage. The lesion was successfully treated using endovascular techniques.


Conceptual framework for the study of parental end-of-life decision making in pediatric blood and marrow transplantation.
To describe a conceptual framework that will facilitate research and practice concerning parental end-of-life decision making in pediatric blood and marrow transplantation (BMT). A review of relevant literature from Ovid, CINAHL, EBSCO, MEDLINE, PsycINFO, and various sociology and theology databases was combined with experiential knowledge. The method of concept and theory synthesis and derivation as described by Walker and Avant was used in the development of this framework. Use of the proposed conceptual framework is expected to provide the organization necessary for thinking, observation, and interpretation of parental end-of-life decision making in pediatric BMT. The ability to describe the process of parental end-of-life decision making in pediatric BMT will help nurses to provide appropriate counseling, education, and support for these children and their families at the end of life. In addition, the process will help nurses to promote the well-being of the children's families after end of life.


Comparing histopathological classification with MYCN, 1p36 and 17q status detected by fluorescence in situ hybridisation from 14 untreated primary neuroblastomas in Singapore.
Neuroblastoma is the most common extracranial solid tumour in children, accounting for about 5.3 percent of all childhood cancers in Singapore. Several genetic abnormalities have been reported as prognostic markers, including amplification of the MYCN gene, deletion of the short arm of chromosome 1 (1p) and gain of the long arm of chromosome 17 (17q). However, the correlation between tumour histology and these genetic parameters remains to be established in our local population. 14 untreated primary neuroblastoma tumours, diagnosed consecutively in our hospital between 2003 and 2007, were included for this study. Tumour tissues were classified histologically as favourable or unfavourable, according to the modification of World Heath Organization Classification of Tumours, by associating the degree of differentiation and mitotic-karyorrhectic index of the neuroblastoma to the age of the patient. Fluorescence in situ hybridisation analysis for MYCN, 1p status and 17q status were subsequently performed on tumour touch imprints. Five tumours with favourable histology were all negative for the three genetic parameters being investigated. The other nine tumours showing unfavourable histology exhibited one or more of the three genetic parameters. All MYCN amplified tumours either had additional 1p deletion and/or 17q gain. Our limited data suggests that 1p deletion and 17q gain are reliable independent parameters correlating with an unfavourable histology and poor clinical outcome. The use of 1p deletion and 17q gain studies, in addition to MYCN amplification studies, should be considered routinely in predicting prognosis in neuroblastomas.


Transformation of Pathology Reports Into the Common Data Model With Oncology Module: Use Case for Colon Cancer.
Common data models (CDMs) help standardize electronic health record data and facilitate outcome analysis for observational and longitudinal research. An analysis of pathology reports is required to establish fundamental information infrastructure for data-driven colon cancer research. The Observational Medical Outcomes Partnership (OMOP) CDM is used in distributed research networks for clinical data; however, it requires conversion of free text-based pathology reports into the CDM's format. There are few use cases of representing cancer data in CDM. In this study, we aimed to construct a CDM database of colon cancer-related pathology with natural language processing (NLP) for a research platform that can utilize both clinical and omics data. The essential text entities from the pathology reports are extracted, standardized, and converted to the OMOP CDM format in order to utilize the pathology data in cancer research. We extracted clinical text entities, mapped them to the standard concepts in the Observational Health Data Sciences and Informatics vocabularies, and built databases and defined relations for the CDM tables. Major clinical entities were extracted through NLP on pathology reports of surgical specimens, immunohistochemical studies, and molecular studies of colon cancer patients at a tertiary general hospital in South Korea. Items were extracted from each report using regular expressions in Python. Unstructured data, such as text that does not have a pattern, were handled with expert advice by adding regular expression rules. Our own dictionary was used for normalization and standardization to deal with biomarker and gene names and other ungrammatical expressions. The extracted clinical and genetic information was mapped to the Logical Observation Identifiers Names and Codes databases and the Systematized Nomenclature of Medicine (SNOMED) standard terminologies recommended by the OMOP CDM. The database-table relationships were newly defined through SNOMED standard terminology concepts. The standardized data were inserted into the CDM tables. For evaluation, 100 reports were randomly selected and independently annotated by a medical informatics expert and a nurse. We examined and standardized 1848 immunohistochemical study reports, 3890 molecular study reports, and 12,352 pathology reports of surgical specimens (from 2017 to 2018). The constructed and updated database contained the following extracted colorectal entities: (1) NOTE_NLP, (2) MEASUREMENT, (3) CONDITION_OCCURRENCE, (4) SPECIMEN, and (5) FACT_RELATIONSHIP of specimen with condition and measurement. This study aimed to prepare CDM data for a research platform to take advantage of all omics clinical and patient data at Seoul National University Bundang Hospital for colon cancer pathology. A more sophisticated preparation of the pathology data is needed for further research on cancer genomics, and various types of text narratives are the next target for additional research on the use of data in the CDM.


Clinical applications of robotic technology in vascular and endovascular surgery.
Emerging robotic technologies are increasingly being used by surgical disciplines to facilitate and improve performance of minimally invasive surgery. Robot-assisted intervention has recently been introduced into the field of vascular surgery to potentially enhance laparoscopic vascular and endovascular capabilities. The objective of this study was to review the current status of clinical robotic applications in vascular surgery. A systematic literature search was performed in order to identify all published clinical studies related to robotic implementation in vascular intervention. Web-based search engines were searched using the keywords "surgical robotics," "robotic surgery," "robotics," "computer assisted surgery," and "vascular surgery" or "endovascular" for articles published between January 1990 and November 2009. An evaluation and critical overview of these studies is reported. In addition, an analysis and discussion of supporting evidence for robotic computer-enhanced telemanipulation systems in relation to their applications in laparoscopic vascular and endovascular surgery was undertaken. Seventeen articles reporting on clinical applications of robotics in laparoscopic vascular and endovascular surgery were detected. They were either case reports or retrospective patient series and prospective studies reporting laparoscopic vascular and endovascular treatments for patients using robotic technology. Minimal comparative clinical evidence to evaluate the advantages of robot-assisted vascular procedures was identified. Robot-assisted laparoscopic aortic procedures have been reported by several studies with satisfactory results. Furthermore, the use of robotic technology as a sole modality for abdominal aortic aneurysm repair and expansion of its applications to splenic and renal artery aneurysm reconstruction have been described. Robotically steerable endovascular catheter systems have potential advantages over conventional catheterization systems. Promising results from applications in cardiac interventions and preclinical studies have urged their use in vascular surgery. Although successful applications in endovascular repair of abdominal aortic aneurysm and lower extremity arterial disease have been reported, published clinical experience with the endovascular robot is limited. Robotic technology may enhance vascular surgical techniques given preclinical evidence and early clinical reports. Further clinical studies are required to quantify its advantages over conventional treatments and define its role in vascular and endovascular surgery.


Effect of hepatitis C virus on C-reactive protein and interleukin-6 in hemodialysis patients.
Patients with end-stage renal disease are at a high risk of hepatitis C virus (HCV) infections. These patients are on maintenance hemodialysis where they are exposed to dialysis fluid and dialysis membrane that generate an acute-phase response, which leads to inflammation, reflected in increased inflammatory markers like C-reactive protein (CRP) and interleukin-6 (IL-6). The aim of this study was to investigate levels of IL-6 and CRP in patients on hemodialysis and to determine effects of HCV on these markers. A total of 43 patients (39.5% men and 60.5% women; age range, 21 to 65 years) on maintenance hemodialysis for a period of at least 3 months were included. Twenty-four of them were HCV positive. Serum IL-6 and CRP were assessed in all patients. Of HCV-positive patients, 11 (45.8%) had high levels of CRP, while 13 (54.2%) had low levels and increased levels of IL-6 (1064 ± 544.2 pg/mL, P = .19). Of 19 HCV-negative patients, 13 (68.4%) had high levels of CRP, while 6 (31.6%) had low levels, and all these patients had low levels of IL-6, as compared to HCV-positive patients. No significant correlation was observed between the levels of CRP or IL-6 and the duration of dialysis. In our study, we found high serum IL-6 and CRP levels in HCV-positive hemodialysis patients, compared with HCV-negative ones. However, we failed to show the significance of these differences. More studies with large sample sizes and evaluation of the other inflammatory markers are warranted.


The AQC database represents a useful tool for quality control and scientific analysis of acute appendicitis.
To ensure a high quality of care in surgery, many surgical departments in Switzerland are members of the working group for quality assurance in surgery (AQC). The purpose of this study was to assess the value of the AQC database as a tool for quality assurance and a source for scientific studies. We had two hypotheses. Firstly that the percentage of laparoscopic appendectomies would have increased over time without an increase in the complication rate and secondly that these procedures would primarily have been performed by residents. All appendectomies performed at the Kantonsspital Olten between 2001 and 2006 were prospectively recorded in the AQC database. 684 appendectomies were performed. We recorded a clear increase in the use of laparoscopic interventions from 51 to 81%. Ninety three percent of these appendectomies were performed by residents or junior faculty members. The main complication were surgical site infection in 3.6% of the open procedures as compared to none in laparoscopic procedures (p <0.001). Intra-abdominal abscess formation was recorded in 2.7% of laparoscopic procedures as compared to 1.8% in open surgery (p = 0.608). The overall complication rate in the study was 5.4% with no statistical difference between open (6.5%) and laparoscopic (4.7%) surgery (p = 0.305). The study clearly shows that the AQC-database offers a wide variety of possibilities for quality assurance and scientific analyses. Our data demonstrate that laparoscopic procedures clearly increased from 2001 to 2006. Appendectomies were mainly performed by residents and junior faculty members. Laparoscopic appendectomy is a safe procedure with a low complication rate and should be applied as a teaching operation during the surgical training.


Scapular dyskinesis increases the risk of future shoulder pain by 43% in asymptomatic athletes: a systematic review and meta-analysis.
It is unclear whether the presence of scapular dyskinesis increases the risk of developing shoulder pain in asymptomatic athletes. To determine whether the presence of scapular dyskinesis in asymptomatic athletes increases the risk of developing shoulder pain by systematic review and meta-analysis. A systematic search was conducted in the Cochrane Library, Embase, PubMed, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database and SPORTDiscus. Prospective studies that assessed athletes for scapular dyskinesis and recorded incidents of shoulder pain were included. Study quality was assessed using the Downs and Black checklist. Meta-analysis was conducted to derive a pooled risk ratio (RR) for the development of shoulder pain in athletes with scapular dyskinesis compared with those without scapular dyskinesis. Five studies were included with a total of 419 athletes. Of the athletes with scapular dyskinesis, 35% (56/160) experienced shoulder pain during the follow-up, whereas 25% (65/259) of athletes without scapular dyskinesis experienced symptoms. The presence of scapular dyskinesis at baseline indicated a 43% increased risk of a shoulder pain event over a 9 to 24 months follow-up (RR=1.43, 95% CI 1.05 to 1.93). Athletes with scapular dyskinesis have 43% greater risk of developing shoulder pain than those without scapular dyskinesis.


DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.
The establishment of DNA methylation patterns requires de novo methylation that occurs predominantly during early development and gametogenesis in mice. Here we demonstrate that two recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, are essential for de novo methylation and for mouse development. Inactivation of both genes by gene targeting blocks de novo methylation in ES cells and early embryos, but it has no effect on maintenance of imprinted methylation patterns. Dnmt3a and Dnmt3b also exhibit nonoverlapping functions in development, with Dnmt3b specifically required for methylation of centromeric minor satellite repeats. Mutations of human DNMT3B are found in ICF syndrome, a developmental defect characterized by hypomethylation of pericentromeric repeats. Our results indicate that both Dnmt3a and Dnmt3b function as de novo methyltransferases that play important roles in normal development and disease.


The gene encoding the common alpha subunit of the four human glycoprotein hormones.
The gene encoding the common alpha subunit of the four human glycoprotein hormones, chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH), has been cloned in a bacteriophage lambda vector. Restriction endonuclease digestion of total human DNA suggests that the common alpha subunit is coded for by a single gene. Three distinct polymorphic hybridization patterns have been observed for this gene in the human population. The cloned gene encompasses a total of 9.4 kilobases (kb) and contains three intervening sequences whose locations have been established by restriction enzyme mapping and by DNA sequencing. One of the intervening sequences is located in the 5' untranslated region, generating a leader sequence that is separated from the rest of the gene by 6.4 kb. The other two intervening sequences are 1.7 and 0.4 kb long and are located within codon number 6, and between codons 67 and 68, respectively. The location of the 5' end of the mature transcript has been established by priming placental mRNA with a restriction fragment obtained from the cloned cDNA. A transcript of similar size for the alpha subunit gene has been detected in both the pituitary, where the gene is expressed for the synthesis of LH, FSH, and TSH, and the placenta, where the gene is expressed for the synthesis of CG. When parts of the 5' untranslated nucleotide sequences of the alpha subunit and the human growth hormone genes are compared a highly homologous region is observed. These otherwise unrelated genes share the common feature that they encode a secreted pituitary polypeptide hormone.


Wrist breadth and homeostasis model assessment of insulin resistance in youth: the Fels Longitudinal Study.
There is biological crosstalk between insulin signaling and bone remodeling pathways, and wrist circumference and bone area were recently found to associate with insulin resistance independent of body mass index (BMI) in overweight/obese children. We aimed to expand on this work by using more specific measures of adiposity for adjustment and examining children with broader range of BMI. We used serial data (1,051 total measures) on 313 non-Hispanic white youth (ages 8-18 y) from the Fels Longitudinal Study with homeostasis model assessment of insulin resistance (HOMA-IR) as the outcome. Internal standard deviation score (SDS) for wrist breadth was evaluated as a predictor of HOMA-IR (log-transformed) before and after adjusting for internal-sample SDSs for BMI, waist circumference (WC), and total body fat (TBF) from dual energy X-ray absorptiometry, in addition to age, sex, Tanner stage, and birth year, using generalized estimating equations. Before additional adiposity adjustment, we found a significant positive association between wrist breadth SDS and log-transformed HOMA-IR (β = 0.13; 95%CI: 0.09-0.17), which remained significant after adjusting for TBF SDS (β = 0.09; 95%CI: 0.05-0.13; P < 0.001), BMI SDS (β = 0.06; 95%CI: 0.02-0.10; P = 0.007), and WC SDS (β = 0.06; 95%CI: 0.02-0.09; P = 0.005). Further work is needed to determine whether simple frame size measures such as wrist breadth may be useful markers of metabolic risk.


Does the histopathologic pattern of the ureteropelvic junction affect the outcome of pyeloplasty.
To investigate the effects of the histopathologic pattern of obstructed ureteropelvic junction (UPJ) specimens, including collagen type 3, elastin, fibrosis and Cajal cells, on the outcome of pyeloplasty. Histopathological specimens obtained following Anderson-Hynes pyeloplasty from 52 patients with intrinsic ureteropelvic junction obstruction (UPJO) between January 2005 and January 2008 were evaluated histopathologically. Patients with extrinsic or secondary UPJO were excluded. Preoperative and postoperative radiographic evaluations were performed either via diuretic renography or intravenous pyelography, or both. Six months post-surgery the patients were divided into 2 groups, as successful surgery (group 1) and unsuccessful surgery (group 2). Histopathological findings (collagen type 3, elastin, fibrosis and Cajal cells) in each group were statistically compared. The study included 52 patients (21 female and 31 male). Mean age of the entire study population was 39.42 ± 14.5 years, versus 39.63 ± 14.9 years in group 1 (n = 47) and 37.4 ± 10.0 years in group 2 (n = 5). Median follow-up was 18 months. There weren't any significant differences in collagen type 3, elastin, fibrosis, or Cajal cells between the 2 groups (P > .05). The histopathologic pattern of UPJ was not a factor associated with the success of pyeloplasty. Based on the present findings, we conclude that surgical technique is more important than the histopathologic pattern of UPJ for the successful treatment of UPJO.


Convolutional networks for fast, energy-efficient neuromorphic computing.
Deep networks are now able to achieve human-level performance on a broad spectrum of recognition tasks. Independently, neuromorphic computing has now demonstrated unprecedented energy-efficiency through a new chip architecture based on spiking neurons, low precision synapses, and a scalable communication network. Here, we demonstrate that neuromorphic computing, despite its novel architectural primitives, can implement deep convolution networks that (i) approach state-of-the-art classification accuracy across eight standard datasets encompassing vision and speech, (ii) perform inference while preserving the hardware's underlying energy-efficiency and high throughput, running on the aforementioned datasets at between 1,200 and 2,600 frames/s and using between 25 and 275 mW (effectively >6,000 frames/s per Watt), and (iii) can be specified and trained using backpropagation with the same ease-of-use as contemporary deep learning. This approach allows the algorithmic power of deep learning to be merged with the efficiency of neuromorphic processors, bringing the promise of embedded, intelligent, brain-inspired computing one step closer.