The physiology of multifactorial problems limiting the establishment of pregnancy in dairy cattle.
The failure of cows to successfully establish pregnancy after insemination is an important limiting factor for the efficiency of dairy production systems. The physiological reasons for this are many and pertain to the post partum and early pregnancy periods. Cows that suffer severe negative energy balance after parturition are prone to diseases (including uterine infection) that are, in part, explained by reduced function of the immune system, having negative consequences for subsequent fertility. In high-producing dairy cows, the duration and intensity of oestrus is low as a consequence of low circulating oestradiol concentrations, and after insemination, high embryo mortality is the single biggest factor reducing calving rates. Embryo mortality occurs as consequences of poor oocyte quality (probably caused by the adverse metabolic environment) and by poor maternal uterine environment (probably caused by carry-over effects of uterine infection and low circulating progesterone concentrations). Immediate improvements in the fertility of lactating cows on many farms can be achieved by applying existing knowledge, but longer-term sustained improvement will require additional knowledge in many areas including the physiology of the tissues that contribute to reproduction.


Lifestyle Intervention's Effect and Predictive Value on Weight Loss for University Employees.
Obesity is a costly and pervasive risk factor that requires attention to reduce chronic disease rates. This study evaluated the effect of a lifestyle medicine intervention, Complete Health Improvement Program (CHIP), on reducing weight, blood pressure, lipid levels, and hemoglobin A1c. A secondary aim was to build a preliminary predictive model for computing new participants' potential weight change from CHIP. We evaluated pre- and post-intervention biometric data of 68 individuals who completed a 10-week CHIP intervention at a Midwestern university clinic. Significant reductions (p < 0.05) were observed in weight, diastolic blood pressure, total cholesterol, low-density lipoprotein, and A1c. Regression analyses indicated that the best linear model for predicting change in weight was a one-predictor model with systolic blood pressure. The CHIP intervention effectively promoted weight loss and meaningful reductions in chronic disease risk factors. Larger samples are needed for future regression analyses to create a more robust linear model.


The hypothalamus and its role in hypertension.
For the majority of hypertensive patients, the etiology of their disease is unknown. The hypothalamus is a central structure of the brain which provides an adaptive, integrative, autonomic, and neuroendocrine response to any fluctuations in physiological conditions of the external or internal environment. Hypothalamic insufficiency leads to severe metabolic and functional disorders, including persistent increase in blood pressure. Here, we discuss alterations in the neurochemical organization of the paraventricular and suprachiasmatic nucleus in the hypothalamus of patients who suffered from essential hypertension and died suddenly due to acute coronary failure. The changes observed are hypothesized to contribute to the pathogenesis of disease.


Expression of Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) Exacerbates Hepatocellular Carcinoma Through Suppressing miR-195.
BACKGROUND Aberrant expression of lncRNA has been suggested to have an association with tumorigenesis. Our study was designed to reveal the underlying connection between lncRNA SNHG1 and hepatocellular carcinoma (HCC) pathogenesis. MATERIAL AND METHODS A total of 122 pairs of HCC tissues (case group) and matched adjacent non-tumor liver tissues (control group) were collected for this study. RT-PCR and in situ hybridization were conducted to investigate differences in lncRNA SNHG1 expression between the case and control group. The expression levels of lncRNA SNHG1 and miR-195 in HepG2 cells transfected with SNHG1-mimic and SNHG1-inhibitor were measured by RT-PCR. The proliferation, invasion, and migration status of HepG2 cells after transfection were assessed through MTT assay, wound healing assay, and Transwell assay, respectively. Whether miR-195 is a direct downstream target of lncRNA SNHG1 was verified by both bioinformatics target gene prediction and dual-luciferase report assay. RESULTS The expression level of lncRNA SNHG1 was remarkably upregulated in HCC tissues and cell lines compared with normal tissues and cell lines. High expression of lncRNA SNHG1 contributed to the downregulation of miR-195 in HepG2 cells. Also, lncRNA SNHG1 exacerbated HCC cell proliferation, invasion, and migration in vitro through the inhibition of miR-195. This suggests that miR-195 is a direct downstream target of lncRNA SNHG1. CONCLUSIONS lncRNA SNHG1 may contribute to the aggravation of HCC through the inhibition of miR-195.


The immunological challenges of cell transplantation for the treatment of Parkinson's disease.
Dopaminergic cell transplantation is an experimental therapy for Parkinson's disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future.


Comparison of DEXA and Bioimpedance for Body Composition Measurements in Nondialysis Patients With CKD.
The aims of this study are (1) to compare dual-energy X-ray absorptiometry (DEXA) and bioimpedance for body composition measurements in nondialysis patients with chronic kidney disease, and (2) to investigate factors associated with any measurement differences. This is a substudy using some baseline data from a randomized controlled clinical trial. One hundred twenty patients (aged 65 ± 14 years) with a measured glomerular filtration rate 8 to 55 mL/min/1.73m2, not on renal replacement therapy, irrespective of age and number of comorbidities, were included from 2011 to 2016. For DEXA measurements, Lunar Prodigy or Lunar iDXA were used. For bioimpedance measurements, body composition monitor (BCM) was used. Glomerular filtration rate was measured with iohexol clearance. Data were analyzed using R software. Bland-Altman analysis was performed to compare the 2 measurements. The measurement difference was DEXA minus BCM. Multiple linear regression analysis was performed to analyze relationships between variables. The estimation of fat-free mass was higher using BCM than DEXA, with a mean difference of -2.8 kg and limits of agreement (mean ± 2 SD) ranging from -12 kg to 6.5 kg. The estimation of fat mass was lower using BCM than DEXA, with a mean difference of 3.1 kg and limits of agreement (mean ± 2 SD) ranging from -6.8 kg to 13 kg. The measurement differences were significantly related to lean tissue index, fat tissue index, extracellular water, intracellular water, extracellular water/intracellular water, total body water, and overhydration. Our study showed a limited agreement between DEXA and bioimpedance, indicating that these 2 measurements are not interchangeable in nondialysis patients with chronic kidney disease. Lean tissue index, fat tissue index, and body water might contribute to the measurement differences, while measured glomerular filtration rate is not a factor associated with the measurement differences for body composition. Thus, we suggest that the same measure of body composition be used over time.


A case of unclassified headache involving bilateral nuchal to frontal pain associated with burning eyes and lacrimation.
A 21-year-old Caucasian male presented to an oral medicine clinic with bilateral nuchal to frontal headache that was associated with burning eyes and lacrimation. Following a string of previous consultations with a variety of specialists, no diagnosis had been made. Treatment was carried out empirically, with the best improvement experienced when the patient was put on a combination of gabapentin and dothiepin treatment. This case highlights the importance of multidisciplinary management of headaches, as well as constant revision of the International Classification of Headache Disorders.


Lineage-Specific Analysis of Syk Function in Autoantibody-Induced Arthritis.
Autoantibody production and autoantibody-mediated inflammation are hallmarks of a number of autoimmune diseases. The K/BxN serum-transfer arthritis is one of the most widely used models of the effector phase of autoantibody-induced pathology. Several hematopoietic lineages including neutrophils, platelets, and mast cells have been proposed to contribute to inflammation and tissue damage in this model. We have previously shown that the Syk tyrosine kinase is critically involved in the development in K/BxN serum-transfer arthritis and bone marrow chimeric experiments indicated that Syk is likely involved in one or more hematopoietic lineages during the disease course. The aim of the present study was to further define the lineage(s) in which Syk expression is required for autoantibody-induced arthritis. To this end, K/BxN serum-transfer arthritis was tested in conditional mutant mice in which Syk was deleted in a lineage-specific manner from neutrophils, platelets, or mast cells. Combination of the MRP8-Cre, PF4-Cre, or Mcpt5-Cre transgene with floxed Syk alleles allowed efficient and selective deletion of Syk from neutrophils, platelets, or mast cells, respectively. This has also been confirmed by defective Syk-dependent in vitro functional responses of the respective cell types. In vivo studies revealed nearly complete defect of the development of K/BxN serum-transfer arthritis upon neutrophil-specific deletion of Syk. By contrast, Syk deletion from platelets or mast cells did not affect the development of K/BxN serum-transfer arthritis. Our results indicate that autoantibody-induced arthritis requires Syk expression in neutrophils, whereas, contrary to prior assumptions, Syk expression in platelets or mast cells is dispensable for disease development in this model.


Distinctive Three-Step Hysteretic Sorption of Ethane with In Situ Crystallographic Visualization of the Pore Forms in a Soft Porous Crystal.
A soft porous Zn(II)-MOF (1) displays distinctive three-step hysteretic breathing behavior under ethane gas pressure at ambient temperatures. In situ single-crystal X-ray diffraction analysis was carried out at 298 K using an environmental gas cell in order to elucidate the different porous forms of the breathing framework under ethane gas. The three different phases were further characterized by pressure-gradient differential scanning calorimetry and variable pressure powder X-ray diffraction analysis.


In vitro susceptibility studies of Cryptococcus neoformans isolated from patients with no clinical response to amphotericin B therapy.
The in vitro activities of three antifungal drugs alone and in combination were evaluated against five isolates of Cryptococcus neoformans using time-kill curves (TKC). The isolates were from AIDS patients who had either died or had failed to show a clinical response during amphotericin B (AMB) treatment. AMB, fluconazole (FCZ) and flucytosine (5FC), and combinations of the drugs (AMB plus 5FC, AMB plus rifampicin (RIF) and FCZ plus 5FC), were evaluated. With all five isolates AMB did not show fungicidal activity; instead, a persistent or tolerant effect was observed. Combinations of AMB plus 5FC and AMB plus RIF showed a clear synergic effect, except for one isolate tested with AMB plus RIF. In contrast, the FCZ plus 5FC combination did not inhibit growth of any isolate.


Sensitivity of the relative-rate test to taxonomic sampling.
Relative-rate tests may be used to compare substitution rates between more than two sequences, which yields two main questions: What influence does the number of sequences have on relative-rate tests and what is the influence of the sampling strategy as characterized by the phylogenetic relationships between sequences? Using both simulations and analysis of real data from murids (APRT and LCAT nuclear genes), we show that comparing large numbers of species significantly improves the power of the test. This effect is stronger if species are more distantly related. On the other hand, it appears to be less rewarding to increase outgroup sampling than to use the single nearest outgroup sequence. Rates may be compared between paraphyletic ingroups and using paraphyletic outgroups, but unbalanced taxonomic sampling can bias the test. We present a simple phylogenetic weighting scheme which takes taxonomic sampling into account and significantly improves the relative-rate test in cases of unbalanced sampling. The answers are thus: (1) large taxonomic sampling of compared groups improves relative-rate tests, (2) sampling many outgroups does not bring significant improvement, (3) the only constraint on sampling strategy is that the outgroup be valid, and (4) results are more accurate when phylogenetic relationships between the investigated sequences are taken into account. Given current limitations of the maximum-likelihood and nonparametric approaches, the relative-rate test generalized to any number of species with phylogenetic weighting appears to be the most general test available to compare rates between lineages.


[Primary angioplasty in acute ST elevation myocardial infarction in the elderly].
Based on data from the literature, it has been suggested that elderly patients with acute myocardial infarction will benefit more from primary angioplasty than from thrombolysis. Data for 100 consecutive patients, age 75 years or more, presenting with an acute ST elevation myocardial infarction (STEMI) without cardiogenic shock and treated with primary angioplasty were analysed retrospectively. Some variables were compared with previously published data on a group of 100 younger patients (mean age 59) with STEMI. Angiographically, the success rate of revascularization was similar between the elderly (mean age 80) and the younger STEMI patients. Mortality, both at 30 days and at 1 year, was higher among the elderly patients compared with the younger (15% vs. 1% and 21% vs. 3% respectively, both p < 0.001). In the same time period, primary angioplasty was performed in seven patients > or = 75 years who presented with cardiogenic shock at admission. All of these died during hospitalization. Technically, the success rate of primary angioplasty in elderly patients with STEMI was similar to that in younger STEMI patients. Mortality after 30 days was significantly higher among the elderly patients, but the mortality rate from 30 days to 1 year after the infarction was similar to that of the same age group in the general population. Patients > or = 75 years presenting with STEMI and cardiogenic shock had no benefit of angioplasty; all died during hospitalization.


Pyogenic spondylitis. Analysis of three surgically treated cases.
During a period of 10 years (1964--1973) three patients developing pyogenic spondylitis were operated on. The patients suffered from severe localized back pain and showed sings of infection, as elevation of temperature and raised ESR. The earliest radiological changes were diagnosed on the average after 3 months. As treatment with antibiotics could not cure the infection, the patients were operated on by evacuation of a vertebral focus, and this measure was complemented with bone transplantation. All patients were cured from the fulminant spondylitis, and two of them returned to regular work. No recurrence was noted during an observation period averaging 8 years. Surgery seems to be indicated in some cases of nonspecific spondylitis, especially when a paravertebral spread of the infection is recorded and antibiotic treatment does not primarily show sufficient effect.


Persistence With Conventional Triple Therapy Versus a Tumor Necrosis Factor Inhibitor and Methotrexate in US Veterans With Rheumatoid Arthritis.
To compare persistence and adherence to triple therapy with the nonbiologic disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), hydroxychloroquine, and sulfasalazine, versus a tumor necrosis factor inhibitor (TNFi) plus MTX in patients with rheumatoid arthritis (RA). Administrative and laboratory data were analyzed for US Veterans with RA initiating triple therapy or TNFi + MTX between January 2006 and December 2012. Treatment persistence 365 days postindex was calculated using 3 definitions. Definition 1 required no gap in therapy of ≥90 days for any drug in the original combination. Definition 2 required no added or switched DMARD, no decrease to nonbiologic DMARD monotherapy, and no termination of all DMARD therapies. Definition 3 was similar to definition 2 but allowed a switch to another drug within the same class. Adherence used a proportion of days covered of ≥80%. Propensity-weighted analysis with matched weights was used to balance covariates. The analysis included 4,364 RA patients (TNFi + MTX, n = 3,204; triple therapy, n = 1,160). In propensity-weighted analysis, patients in the TNFi + MTX group were significantly more likely than patients in the triple therapy group to satisfy all persistence criteria in definition 1 (risk difference [RD] 13.1% [95% confidence interval (95% CI) 9.2-17.0]), definition 2 (RD 6.4% [95% CI 2.3-10.5]), and definition 3 (RD 9.5% [95% CI 5.5-13.6]). Patients in the TNFi + MTX group also exhibited higher adherence during the first year (RD 7.2% [95% CI 3.8-10.5]). US Veterans with RA were significantly more likely to be persistent and adherent to combination therapy with TNFi + MTX than triple therapy with nonbiologic DMARDs.


A Phase II, Randomized, Multicenter Study Comparing 10 Months versus 4 Months of Degarelix Therapy in Prolonging the Off Treatment Interval in Men with Localized Prostate Cancer Receiving Intermittent Androgen Deprivation Therapy for Biochemical Recurrence following Radical Local Therapy.
Clinical trials in men initiating intermittent androgen deprivation therapy have used a range of induction durations between 3 and 12 months. We sought to determine whether the duration of induction androgen deprivation therapy would influence the duration of the off treatment interval and the recovery of serum testosterone. This was a prospective, randomized, open label study. Men with biochemical recurrence after local therapy for prostate cancer and a negative bone scan were randomized to 4 and 10 months of monthly degarelix. The first dose was 240 mg and subsequent doses were 80 mg per month. Quality of life was evaluated by the I-PSS (International Prostate Symptom Score), the PAS-SFI (Problem Assessment Scale of the Sexual Function Index) and the FACT-P (Functional Assessment of Cancer Therapy-Prostate). A total of 90 patients were randomized, including 43 to 4 months and 47 to 10 months of treatment. There was no difference in any relevant baseline laboratory parameter, including prostate specific antigen and testosterone. There was no difference between the 2 treatment groups in time off treatment (HR 1.51, 95% CI 0.60-3.84, p = 0.38). Actuarial median time to testosterone recovery to 8.0 nmol/l or greater was 8.05 months (95% CI 4.34-39.89) in the 10-month treatment arm and 6.24 months (95% CI 5.45-15.90) in the 4-month treatment arm. The log rank test showed no statistical significance between the 2 treatment groups in time to testosterone recovery (p = 0.8392). There was no difference in the testosterone recovery rate between the 2 arms. Men younger than 65 years had a considerably shorter interval off treatment and time to testosterone recovery. There was a lesser adverse effect on quality of life at the end of treatment in the 4-month than in the 10-month arm. In men with biochemical recurrence who initiated intermittent androgen deprivation therapy with degarelix no difference was observed in the duration of the off treatment interval or the rate of testosterone recovery whether they received 4 or 10 months of induction androgen deprivation therapy.


Congenital long QT 3 in the pediatric population.
There is insufficient knowledge concerning long-QT (LQT) 3 in the pediatric population to determine whether recommendations for more aggressive therapy in these patients are appropriate. An international multicenter review of 43 children with cardiac sodium channel (SCN5A) mutations and clinical manifestations of LQT syndrome without overlap of other SCN5A syndromes was undertaken to describe the clinical characteristics of LQT3 in children. Patients were aged 7.6 ± 5.9 years at presentation and were followed for 4.7 ± 3.9 years. There was significant intrasubject corrected QT interval (QTc) variability on serial electrocardiography. Forty-two percent presented with severe symptoms or arrhythmia and exhibited longer QTc intervals compared to asymptomatic patients. None of the 14 patients who underwent primary prevention implantable cardioverter-defibrillator (ICD) implantation received appropriate shocks in 41 patient-years of follow-up, while 2 of 6 patients who underwent secondary prevention ICD implantation received appropriate shocks in 30 patient-years of follow-up. Half of patients who underwent ICD implantation experienced inappropriate shocks or ICD-related complications. Mexiletine significantly shortened the QTc interval, and QTc shortening was greater in patients with longer pretreated QTc intervals. Two ICD patients with frequent appropriate ICD shocks showed immediate clinical improvement, with elimination of appropriate ICD shocks after mexiletine loading. In conclusion, severe symptoms are common in children with LQT3 and are associated with longer QTc intervals. ICD implantation is associated with significant morbidity. Mexiletine shortens the QTc interval, and it may be beneficial.


Plant reproductive systems and evolution during biological invasion.
Recent biological invasions provide opportunities to investigate microevolution during contemporary timescales. The tempo and scope of local adaptation will be determined by the intensity of natural selection and the amounts and kinds of genetic variation within populations. In flowering plants, genetic diversity is strongly affected by interactions between reproductive systems and stochastic forces associated with immigration history and range expansion. Here, we explore the significance of reproductive system diversity for contemporary evolution during plant invasion. We focus in particular on how reproductive modes influence the genetic consequences of long-distance colonization and determine the likelihood of adaptive responses during invasion. In many clonal invaders, strong founder effects and restrictions on sexual reproduction limit opportunities for local adaptation. In contrast, adaptive changes to life-history traits should be a general expectation in both outbreeding and inbreeding species. We provide evidence that evolutionary modifications to reproductive systems promote the colonizing ability of invading populations and that reproductive timing is an important target of selection during range expansion. Knowledge of the likelihood and speed at which local adaptation evolves in invasive plants will be particularly important for management practices when evolutionary changes enhance ecological opportunities and invasive spread.


Effect of heat stress on 2-hydroxy-4-(methylthio)butanoic acid and DL-methionine absorption measured in vitro.
The objective of the present experiments was to determine the biochemical basis for preliminary chick performance data, which indicate an ameliorative effect of 2-hydroxy-4-(methylthio)butanoic acid (HMB) when compared with DL-methionine (DLM) fed during hot conditions. In vitro passage of HMB or DLM across intact segments of small intestine from either control (thermoneutral, TN) or heat-stressed (HS) birds was used as a model for intestinal absorption. For DLM placed in the lumen, appearance in the outside buffer was reduced when using intestine from HS birds compared with tissue from TN birds. In contrast, the appearance of HMB in the outside buffer was greater using HS intestine, resulting in a substrate by environment interaction (P < .01). Slices of everted small intestine from TN and HS birds were used to study epithelial uptake of methyl labeled 14C-DLM by three transport pathways: diffusion, carrier-specific energy- and sodium-independent uptake (ESI), and carrier-specific energy- and sodium-dependent uptake (ESD). Correcting for extracellular volume, total epithelial uptake of 14C-DLM (diffusion plus ESI plus ESD) was reduced by 34% in HS intestine (P < .05). Energy-dependent uptake was observed to decrease by 87% in HS (P < .05). Energy-independent uptake was increased (136%, HS versus TN, P < .05), but not enough to compensate for the decrease in ESD uptake. Intestinal transport systems for glucose and leucine were also observed to change during HS, suggesting a role for cellular transport changes in the performance reduction associated with HS.


Kinetics of intramembrane charge movement and conductance activation of batrachotoxin-modified sodium channels in frog node of Ranvier.
Sodium current and intramembrane gating charge movement (Q) were monitored in voltage-clamped frog node of Ranvier after modification of all sodium channels by batrachotoxin (BTX). Sodium current activation followed a single-exponential time course, provided a delay was interposed between the onset of the step ON depolarization and that of the current change. The delay decreased with increased ON depolarization and, for a constant ON depolarization, increased with prehyperpolarization. ON charge movement followed a single-exponential time course with time constants tau Q,ON slightly larger than tau Na, ON. For pulses between -70 and -50 mV, tau Q,ON/tau Na,ON = 1.14 +/- 0.08. The OFF charge movement and OFF sodium current tails after a depolarizing pulse followed single-exponential time courses, with tau Q, OFF larger than tau Na, OFF. tau Q,OFF/tau Na,OFF increased with OFF voltage from 1 near -100 mV to 2 near -160 mV. At a set OFF potential (-120 mV), both tau Q,OFF and tau Na,OFF increased with ON pulse duration. The delay in INa activation and the effect of ON pulse duration on tau Q,OFF and tau Na,OFF are inconsistent with a simple two-state, single-transition model for the gating of batrachotoxin-modified sodium channels.


Effect of saliva fluid properties on pathogen transmissibility.
With an increasing body of evidence that SARS-CoV-2 is an airborne pathogen, droplet character formed during speech, coughs, and sneezes are important. Larger droplets tend to fall faster and are less prone to drive the airborne transmission pathway. Alternatively, small droplets (aerosols) can remain suspended for long time periods. The small size of SARS-CoV-2 enables it to be encapsulated in these aerosols, thereby increasing the pathogen's ability to be transmitted via airborne paths. Droplet formation during human respiratory events relates to airspeed (speech, cough, sneeze), fluid properties of the saliva/mucus, and the fluid content itself. In this work, we study the fluidic drivers (fluid properties and content) and their influence on factors relating to transmissibility. We explore the relationship between saliva fluid properties and droplet airborne transmission paths. Interestingly, the natural human response appears to potentially work with these drivers to mitigate pathogen transmission. In this work, the saliva is varied using two approaches: (1) modifying the saliva with colloids that increase the viscosity/surface tension, and (2) stimulating the saliva content to increased/decreased levels. Through modern experimental and numerical flow diagnostic methods, the character, content, and exposure to droplets and aerosols are all evaluated. The results indicate that altering the saliva properties can significantly impact the droplet size distribution, the formation of aerosols, the trajectory of the bulk of the droplet plume, and the exposure (or transmissibility) to droplets. High-fidelity numerical methods used and verify that increased droplet size character enhances droplet fallout. In the context of natural saliva response, we find previous studies indicating natural human responses of increased saliva viscosity from stress and reduced saliva content from either stress or illness. These responses both favorably correspond to reduced transmissibility. Such a finding also relates to potential control methods, hence, we compared results to a surgical mask. In general, we find that saliva alteration can produce fewer and larger droplets with less content and aerosols. Such results indicate a novel approach to alter SARS-CoV-2's transmission path and may act as a way to control the COVID-19 pandemic, as well as influenza and the common cold.


A search for the optimal stimulus.
How do stimulus size and item number relate to the magnitude and direction of error on center estimation and line cancellation tests? How might this relationship inform theories concerning spatial neglect? These questions were addressed by testing twenty patients with right hemisphere lesions, eleven with left hemisphere lesions and eleven normal control subjects on multiple versions of center estimation and line cancellation tests. Patients who made large errors on these tests also demonstrated an optimal or pivotal stimulus value, i.e., a particular size center estimation test or number of lines on cancellation that either minimized error magnitude relative to other size stimuli (optimal) or marked the boundary between normal and abnormal performance (pivotal). Patients with right hemisphere lesions made increasingly greater errors on the center estimation test as stimuli were both larger and smaller than the optimal value, whereas those with left hemisphere lesions made greater errors as stimuli were smaller than a pivotal value. In normal subjects, the direction of errors on center estimation stimuli shifted from the right of true center to the left as stimuli decreased in size (i.e., the crossover effect). Right hemisphere lesions exaggerated this effect, whereas left hemisphere lesions diminished and possibly reversed the direction of crossover. Error direction did not change as a function of stimulus value on cancellation tests. The demonstration of optimal and pivotal stimulus values indicates that performances on center estimation and cancellation tests in neglect are only relative to the stimuli used. In light of other studies, our findings indicate that patients with spatial neglect grossly overestimate the size of small stimuli and underestimate the size of large stimuli, that crossover represents an "apparent" shift in error direction that actually results from normally occurring errors in size perception, and that the left hemisphere is specialized for one aspect of size estimation, whereas the right performs dual roles.


The role of context in the processing of alcohol-relevant cues.
In line with learning theories of drug addiction, drug-related cues may be viewed as important motivators of continued drug use. They may be differentially effective depending on the context and motivational significance. The present study aimed to test the significance of different contexts in modulating alcohol-related cue reactivity. Pictures depicting alcohol intake or its paraphernalia and pictures without any relation to alcohol intake were varied to depict physical and social contexts or different consumptive contexts associated with full/half-full/empty alcohol beverage containers. We obtained ratings of craving, valence and arousal of the cues as well as skin conductance responses (SCRs) and startle reflex modulation measures from 21 abstinent alcohol-dependent patients, recruited from an addiction treatment center, and 21 matched healthy controls. Social scenes and full glasses or bottles were rated as more pleasant and arousing compared with neutral drinking situations and empty glasses or bottles in patients. Furthermore, we found a decreased startle reflex magnitude to social compared with neutral drinking situations, and both higher SCRs and decreased startle reflex magnitude to full compared with empty glasses or bottles in patients versus controls. These results show that both physical and social and consumptive contexts differentially influence cue reactivity in abstinent alcohol-dependent patients with both social and pub-related physical contexts, and the initial consumptive context eliciting the most appetitive and arousing responses. These data have not only important implications for our understanding of the role of learning in drug dependence but also for treatment, which needs to take these factors into account.


[Molecular genetic and bacteriological methods for the diagnosis of multidrug resistant M. tuberculosis].
For the early diagnosis of multidrug resistant tuberculosis, 67 sputum samples obtained from primary patients with different clinical forms of pulmonary tuberculosis were examined by the molecular genetic test using the TB-Biochip test system. Having a high sensitivity and specificity, the molecular genetic test for determining the drug sensitivity of Mycobacterium tuberculosis substantially accelerates its diagnosis (2-3 days) before the real-time mode of a patient's admission to the clinic. The method allows identification of mutations in the rpoB (resistance to R), katG, inhG, and ahpC (resistance to H) genes, which permits timely correction of performed specific treatment.


Early warning signals in psychopathology: what do they tell?
Despite the increasing understanding of factors that might underlie psychiatric disorders, prospectively detecting shifts from a healthy towards a symptomatic state has remained unattainable. A complex systems perspective on psychopathology implies that such symptom shifts may be foreseen by generic indicators of instability, or early warning signals (EWS). EWS include, for instance, increasing variability, covariance, and autocorrelation in momentary affective states-of which the latter was studied. The present study investigated if EWS predict (i) future worsening of symptoms as well as (ii) the type of symptoms that will develop, meaning that the association between EWS and future symptom shifts would be most pronounced for congruent affective states and psychopathological domains (e.g., feeling down and depression). A registered general population cohort of adolescents (mean age 18 years, 36% male) provided ten daily ratings of their affective states for 6 consecutive days. The resulting time series were used to compute EWS in feeling down, listless, anxious, not relaxed, insecure, suspicious, and unwell. At baseline and 1-year follow-up, symptom severity was assessed by the Symptom Checklist-90 (SCL-90). We selected four subsamples of participants who reported an increase in one of the following SCL-90 domains: depression (N = 180), anxiety (N = 192), interpersonal sensitivity (N = 184), or somatic complaints (N = 166). Multilevel models showed that EWS in feeling suspicious anticipated increases in interpersonal sensitivity, as hypothesized. EWS were absent for other domains. While the association between EWS and symptom increases was restricted to the interpersonal sensitivity domain, post hoc analyses showed that symptom severity at baseline was related to heightened autocorrelations in congruent affective states for interpersonal sensitivity, depression, and anxiety. This pattern replicated in a second, independent dataset. The presence of EWS prior to symptom shifts may depend on the dynamics of the psychopathological domain under consideration: for depression, EWS may manifest only several weeks prior to a shift, while for interpersonal sensitivity, EWS may already occur 1 year in advance. Intensive longitudinal designs where EWS and symptoms are assessed in real-time are required in order to determine at what timescale and for what type of domain EWS are most informative of future psychopathology.


Implementing a DRG-driven acuity system for nurse staffing under prospective hospital payment.
The "DRG-Nursing Unit Manager" is a multifunctional microcomputer software product designed for the effective management of nursing under a DRG prospective payment environment. The system's signature is its simplicity and versatility, and will prove to be a significant management tool for the nursing department. Written to execute on the IBM-PC-XT microcomputer, the nurse can start an application, enter patient demographics, assign Major Diagnostic Category (MDC) and Diagnosis Related Group (DRG) numbers, or make report selections. With a minimal amount of keyboard usage the system collects and saves key data fields, retrieves nursing measures and length of stay norms, and produces reports on a demand basis. The primary report produced by the system is a patient census listing with expected nursing intensities per patient for the next shift which is converted to a staffing projection for the upcoming three shifts for the existing census. The system also allows the costing out of nursing services and produces charge-equivalent statistics so that the nursing station can function as a revenue-producing center. Such an approach permits the identification of DRGs which are "winners" or "losers" under routine care costs.


Perceptions of quality of communication in family interactions in neurocritical care.
Given the challenges of patient-provider communication in neurocritical care lacking robust decision-making tools on prognostication, we investigated concordance in perceptions of communication among participants in family discussions and assess the different domains of communication that affect these perceptions. Prospective observational study conducted over 4 months in a tertiary-level academic medical center neurocritical care unit. Our study involved family discussions regarding plan of care for admitted patients observed by a neutral observer. All participants completed a survey. The first four questions rated the understanding of the discussion and general satisfaction; the remaining questions were open-ended to assess the quality of communication by the physician leading the discussion. Responses were scored and compared among participants using a Likert scale. A difference of < 1 in scores among participants was rated as concordance, whereas that of > 1 was designated as discordance. All open-ended responses were classified into six domains. We observed 35 family discussions. Questions 1 to 3 inquiring on general satisfaction, impact, and understanding of treatment options yielded 99 cross-comparisons per question (297 compared responses). Most responses were either "Strongly Agree" or "Agree," with "Neutral" or "Disagree" responses being more prevalent in Question 2 regarding the impact of the conversation. Overall concordance of responses between participants was 88% with a lower rate of concordance (72%) on Q2. Further open-ended questions queried observers on specific physician-spoken content, and answers were analyzed to identify domains that affected the perception of quality of communication. Education was the most frequently cited domain of communication in response to open-ended questions. Among family and neutral observers, empathy was frequently listed, whereas providers more often listed family engagement. Overall, satisfaction was high among providers, families, and the observer regarding the quality of communication during family discussions in the unit. Perceptual differences emerged over whether this communication impacted healthcare decision-making during that encounter.


The utilization of research evidence in Health Workforce Policies: the perspectives of Portuguese and Brazilian National Policy-Makers.
The production of knowledge on Human Resources for Health (HRH) issues has increased exponentially since 2000 but integration of the research in the policy-making process is often lagging. We looked at how research on HRH contributes or not to inform policy decisions and interventions affecting the health workforce in Portugal and Brazil. We designed a comparative case study of semi-structured interviews with present and past national decision-makers, policy advisors and researchers. Issues explored included the existence of a national HRH policy and the use, or non-use, of research evidence by policy makers and reasons to do so. Interviews were audio recorded, transcribed, anonymized and analysed thematically. Policy-makers in Brazil recognize a greater use of evidence in the process of defining HRH policy when compared to Portugal's. But the existence of formal instruments to support policy development is not sufficient to ensure that policies are informed by evidence. In both countries the importance of the use of evidence in the formulation of policies was recognized by policy-makers. However, the influence of other factors, such as political pressures from various lobby groups and from the media and the policy short timeframe which requires rapid responses, is predominant.


Effectiveness of acupuncture versus spinal-epidural anesthesia on labor pain: a randomized controlled trial.
To evaluate the effectiveness of acupuncture analgesia (AA) compared with combined spinal-epidural anesthesia (CSEA) for labor pain relief and labor outcomes. We evaluated 131 primiparous women who received respiratory guidance during maternal uterine contractions and received either AA (n = 43), CSEA (n = 45), or no additional treatment (control, n = 43). The groups were compared regarding visual analog scale (VAS) scores for abdominal and back pain, and labor outcomes. The abdominal VAS scores of the AA and CSEA groups were significantly lower than that of the control group. In addition, the VAS scores of the CSEA group were significantly lower than that of the AA group at 10 and 60 min after intervention. The back pain VAS scores of the AA and CSEA groups were significantly lower than that of the control group at 5, 10, and 60 min after intervention. The duration of the active phase of labor in the CSEA group was significantly longer than that of the AA and control groups. The rates of oxytocin use (4.70%), urinary retention (4.70%), and postpartum hemorrhage [(273.7 ± 53.6) mL] in the AA group were significantly lower than in the CSEA group [46.70%, 24.20%, and (320.0 ± 85.6) mL, respectively]. Both AA and CSEA were effective for labor pain relief, CSEA provided more effective pain relief, while AA was associated with a shorter duration of labor and fewer adverse effects.and each has its advantages and disadvantages.


The mechanism of noradrenergic alpha 1 excitatory modulation of pontine reticular formation neurons.
The alpha 1 adrenergic receptor occurs in all major divisions of the CNS and is thought to play a role in all behaviors influenced by norepinephrine (NE). In the medial pontine reticular formation (mPRF), the proposed site of adrenergic enhancement of startle responses (Davis, 1984), alpha 1 agonists excite most neurons (Gerber et al., 1990). We here report that alpha 1 excitation results from a reduction of a voltage- and calcium-dependent potassium current, not previously recognized as ligand-modulated. The calcium sensitivity is suggested by its antagonism with Mg2+, Cd2+, Ba2+, low concentrations of tetraethylammonium, and charybdotoxin. The voltage sensitivity of this conductance falls within the membrane potential range critical to action potential generation. Based on this voltage sensitivity, the change in repetitive firing characteristics may be predicted according to a mathematical model of the mPRF neuronal electrophysiology. The predicted response to a 50% decrease in the phenylephrine (PE)-sensitive conductance is similar to the observed responses, with respect to both the current response under voltage-clamp conditions and alterations of the AHP and frequency/current curve. In contrast, modeling a reduction of a voltage-insensitive leak current predicts none of these changes. Thus, the noradrenergic reduction of this current depolarizes the membrane, increases the likelihood of an initial response to depolarizing input, and increases firing rate during sustained depolarization in a manner consistent with an NE role as an excitatory neuromodulator of the mPRF.


Diverse Functions and Mechanisms of Pericytes in Ischemic Stroke.
Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke. Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided. During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery. This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets.


Detrusor overactivity assessment using ultrasound bladder vibrometry.
Objective. Detrusor overactivity (DO) is a urodynamic observation characterized by fluctuations in detrusor pressure (Pdet) of the bladder. Although detecting DO is important for the management of bladder symptoms, the invasive nature of urodynamic studies (UDS) makes it a source of discomfort and morbidity for patients. Ultrasound bladder vibrometry (UBV) could provide a direct and noninvasive means of detecting DO, due to its sensitivity to changes in elasticity and load in the bladder wall. In this study, we investigated the feasibility and applying UBV toward detecting DO.Approach. UBV and urodynamic study (UDS) measurements were collected in 76 neurogenic bladder patients (23 with DO). Timestamped group velocity squared (cg2) data series were collected from UBV measurements. ConcurrentPdetdata series were identically analyzed for comparison and validation. A processing approach is developed to separate transient fluctuations in the data series from the larger trend of the data and a DO index is proposed for characterizing the transient peaks observed in the data.Main Results.Applying the DO index as a classifier for DO produced sensitivities and specificities of 0.70 and 0.75 forcg2data series and 0.70 and 0.83 forPdetdata series respectively.Significance. It was found that DO can be feasibly detected from data series of timestamped UBV measurements. Collectively, these initial results are promising, and further refinement to the UBV measurement process is likely to improve and clarify its capabilities for noninvasive detection of DO.


Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum.
We have examined the relative roles of the macrophage (M phi) plasma membrane receptor for the cleaved third complement component (iC3b, CR3) and of the mannosyl/fucosyl receptor (MFR) in binding and ingestion of Leishmania donovani. In the absence of exogenous complement, the binding and ingestion of promastigotes, which are good activators of the alternative complement pathway, were inhibited by the anti-CR3 monoclonal antibody M1/70, by the Fab portion of an anti-C3 antibody, or by the nucleophile, sodium salicyl hydroxamate, an inhibitor of C3 fixation. This provides strong evidence that M phi-derived, cleaved C3 (iC3b) present on the promastigote surface mediates binding to CR3. Equivalent inhibition of promastigote binding and ingestion was also observed using the soluble inhibitors of MFR activity, mannan or ribonuclease B. No additive effect for blocking the two M phi receptors simultaneously was observed. For amastigotes, which are poor activators of the alternative pathway, a lesser but nevertheless equivalent effect was observed for the three soluble inhibitors of CR3-mediated binding vs. the two soluble inhibitors of MFR-mediated binding. Modulation experiments in which either CR3 or MFR had been rendered inaccessible demonstrated that both receptors must be present on the segment of M phi membrane to which the parasite binds. The combined function of these two distinct M phi receptors may provide a general mechanism for recognition and ingestion of other pathogenic protozoa known to activate the alternative pathway.


Clinical experience with the soybean protein diet in the treatment of hypercholesterolemia.
The efficacy of the total substitution of animal proteins with a textured soybean protein in hypercholesterolemic individuals was assayed in 42 in-patients and 18 out-patients. The in-patients studied followed one of three different crossover protocols: in protocol A, the soybean diet was compared with a standard low lipid diet; protocol B compared two soybean diets, one with added cholesterol, one without; and protocol C compared a soybean diet containing a high P/S fatty acid ratio to one with a low P/S ratio. In all three protocols, the soybean regimen provided valid and reproducible hypocholesterolemic effects that were not modified by the addition of cholesterol. P/S variations appeared, however, to modify the final effect: soybean definitely had a decreased effectiveness with a low P/S (0.1) regimen. The overall plasma cholesterol changes in the 42 in-patients after 3 weeks on the different soybean diet protocols was -20%. Patients with type IIA and IIB hypercholesterolemia provided almost equivalent results, whereas patients with mixed phenotypes (IIB-III) appeared somewhat more sensitive to the dietary effect. Cholesterol decreased mostly in the low density lipoprotein fraction, but some very low density lipoprotein changes were also noted upon variation of the P/S ratio. The out-patients studied provided less satisfactory results. possibly due to the difficulty of adequately complying with the diet. These studies indicate that treatment with the soybean diet is an effective regimen for inducing a significant cholesterol reduction in type II patients refractory to standard low lipid regimens.


Alphab-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions.
We present the first comparative analysis of serum immunoglobulin G reactivity profiles against the full spectrum of human myelin-associated proteins in multiple sclerosis patients and healthy control subjects. In both groups, serum antibodies display a consistent and prominent reaction to alphaB-crystallin (CRYAB) versus other myelin proteins. As an apparently major target for the adaptive immune system in humans, CRYAB selectively accumulates in oligodendrocytes, but not in astrocytes, or axons in so-called preactive multiple sclerosis lesions. These are clusters of activated HLA-DR-expressing microglia in myelinated normal-appearing white matter with no obvious leukocyte infiltration. They are found in most multiple sclerosis patients at all stages of disease. In these lesion areas, CRYAB in oligodendrocytes may come directly in contact with activated HLA-DR+ microglia. We demonstrate that CRYAB activates innate responses by microglia by stimulating the secretion of leukocyte-recruiting factors, including tumor necrosis factor, interleukin 17, CCL5, and CCL1, and immune-regulatory cytokines such as interleukin 10, transforming growth factor-beta, and interleukin 13. Together, these data suggest that CRYAB accumulation in preactive lesions may be part of a reversible reparative local response that involves both oligodendrocytes and microglia. At the same time, however, accumulated CRYAB may represent a major target for adaptive immune responses that could contribute to progression of preactive lesions to a stage of demyelination.


Experimental schistosomiasis mansoni: electrophoretic studies on serum proteins before and after administration of oxamniquine.
By means of electrophoresis quantitative estimation of serum protein components were made at various intervals before and after treatment with oxamniquine. During infection of mice with S. mansoni serum protein fractions showed marked alterations. Significant increase of total protein, alpha-2 globulin and beta globulin started at week 4 and alpha-1 globulin and gamma globulin at week 6. The significant decrease of globulins at week 6 resulted in reduced albumin globulin ratios. Some of these changes developed during maturation of worms and became more evident with initiation of egg deposition. The possible cause of these variations and their significance were discussed. Oxamniquine treatment of infected mice inhibited such alterations. Administration of the drug to normal mice was followed by temporary increase of serum albumin.


Closed-loop insulin delivery: towards improved diabetes care.
The prevalence of type 1 diabetes is escalating worldwide. Novel therapies and management strategies are needed to reduce associated morbidity. Aggressive blood glucose lowering using conventional insulin replacement regimens is limited by the risk of hypoglycemia. Even the most motivated patients may struggle to manage day-to-day variability in insulin requirements. The artificial pancreas or closed-loop insulin delivery may improve outcomes, building on recent technological progress and combining continuous glucose monitoring with insulin pump therapy. So far, closed-loop prototypes have been evaluated under controlled conditions suggesting improved glucose control and a reduced risk of hypoglycemia. Limitations include suboptimal accuracy and reliability of continuous glucose monitors and delays associated with subcutaneous insulin delivery. Outpatient evaluation is required as the next step, leading to deployment into clinical practice.


Double-sector Lorenz plot scattering in an R-R interval analysis of patients with chronic atrial fibrillation: incidence and characteristics of vertices of the double-sector scattering.
Animal experiments have demonstrated that the minimum R-R interval during atrial fibrillation is proportional to the functional refractory period of the atrioventricular node. On Lorenz plots, atrial fibrillation is characterized by sector-shaped scattering; the vertex of the sector (ie, the minimum R-R interval) represents the functional refractory period. According to the atrioventricular nodal dual-pathway theory, it was hypothesized that the dual atrioventricular nodal pathways associated with chronic atrial fibrillation represent two vertices with two sectors. Detection of two-sector Lorenz plot scattering was attempted in 48 patients with chronic atrial fibrillation who underwent 24-hour ambulatory electrocardiography. Lorenz plot scattering was constructed by means of a computer. Two sectors, suggesting dual pathways, were detected in 19 (40%) of the 48 patients. The two vertices, located at 388 +/- 61 ms (mean +/- SD) and 580 +/- 60 ms were considered to represent the functional refractory periods of the fast and slow pathways, respectively. The vertex indicating the fast pathway showed greater circadian variation than that indicating the slow pathway. In one patient with dual-sector Lorenz plot scattering, whose atrial fibrillation spontaneously converted to sinus rhythm, an electrophysiologic study demonstrated dual atrioventricular nodal pathways. Thus, the Lorenz plot analysis identified two sectors, indicating the dual pathways, in approximately 40% of the patients with chronic atrial fibrillation, and the characteristics of the functional refractory periods of both pathways were estimated from the characteristics of the vertices. Although this study did not provide direct evidence of the dual atrioventricular nodal pathways, the analysis of Lorenz plot scattering may be clinically useful for studying the effects of drugs and/or ablation on the ventricular response in patients with atrial fibrillation based on the dual atrioventricular nodal pathway theory.


Validation of an Electronic Visual Analog Scale mHealth Tool for Acute Pain Assessment: Prospective Cross-Sectional Study.
Accurate measurement of pain is required to improve its management and in research. The visual analog scale (VAS) on paper format has been shown to be an accurate, valid, reliable, and reproducible way to measure pain intensity. However, some limitations should be considered, some of which can be implemented with the introduction of an electronic VAS version, suitable to be used both in a tablet and a smartphone. This study aimed to validate a new method of recording pain level by comparing the traditional paper VAS with the pain level module on the newly designed Interactive Clinics app. A prospective observational cross-sectional study was designed. The sample consisted of 102 participants aged 18 to 65 years. A Force Dial FDK 20 algometer (Wagner Instruments) was employed to induce mild pressure symptoms on the participants' thumbs. Pain was measured using a paper VAS (10 cm line) and the app. Intermethod reliability estimated by ICC(3,1) was 0.86 with a 95% confidence interval of 0.81 to 0.90, indicating good reliability. Intramethod reliability estimated by ICCa(3,1) was 0.86 with a 95% confidence interval of 0.81 to 0.90, also indicating good reliability. Bland-Altman analysis showed a difference of 0.175 (0.49), and limits of agreement ranged from -0.79 to 1.14. The pain level module on the app is highly reliable and interchangeable with the paper VAS version. This tool could potentially help clinicians and researchers precisely assess pain in a simple, economic way with the use of a ubiquitous technology.


Lumbar discogenic pain: state-of-the-art review.
To test the null hypotheses that: lumbar intervertebral discs cannot be a source of pain; discs are not a source of pain; painful lumbar discs cannot be diagnosed; and there is no pathology that causes discogenic pain. Philosophical essay and discourse with reference to the literature. Anatomic and physiologic evidence denies the proposition that disc cannot be a source of pain. In patients with back pain, discs can be source of pain. No studies have refuted the ability of disc stimulation to diagnose discogenic pain. Studies warn only that disc stimulation may have a false-positive rate of 10% or less. Internal disc disruption is the leading cause of discogenic pain. Discogenic pain correlates with altered morphology on computerized tomography scan, with changes on magnetic resonance imaging, and with internal biophysical features of the disc. The morphological and biophysical features of discogenic pain have been produced in biomechanics studies and in laboratory animals. All of the null hypotheses that have been raised against the concept of discogenic pain and its diagnosis have each been refuted by one or more studies. Although studies have raised concerns, none has sustained any null hypothesis. Discogenic pain can occur and can be diagnosed if strict operational criteria are used to reduce the likelihood of false-positive results.


[E-cadherin expression and CDH1 promoter methylation in sporadic and hereditary gastric cancer].
To evaluate the role of E-cadherin (E-cad) and CDH1 gene encoding E-cad in the occurrence of sporadic or hereditary gastric cancer. Nineteen normal gastric mucosal issue specimens, 19 specimens of hereditary gastric cancer (diagnosed according to ICG-HGC criteria), and 19 specimens of sporadic gastric cancer examined for E-cad expression and CDH1 promoter methylation using immunohistochemistry and methylation-specific PCR (MSP). The protein expression of E-cad were significantly reduced in both of the cancer tissues (P<0.001) compared with that in the normal gastric mucosal tissues, and showed no significant difference between the two cancers (P=0.84). CDH1 promoter hypermethylation was found in 10 out of the 19 hereditary gastric cancer tissues, a rate significantly higher than that in sporadic gastric cancer tissues (3/19, P<0.01). CDH1 promoter hypermethylation is probably an important factor contributing to reduced E-cad expression in sporadic gastric cancer but not in hereditary gastric cancer.


Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8.
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.


Disruption of segmentation in a short germ insect embryo. I. The location of abnormalities induced by heat shock.
The effect of heat shock (15 min at 48 degrees C) on segmentation has been investigated in the short germ embryo of the locust (Schistocerca gregaria). Prior to formation of the germ anlage and at the disc stage heat shock considerably reduced the survival of eggs but appeared to have little effect upon segmentation. At later stages heat shock had no effect on survival but resulted in disruptions of the segmental pattern. The location of abnormal segments depended upon the stage at heat shock and the number affected depended on its severity. A constant number of normal segments developed between the last segment visible at the time of heat shock and the first abnormal segment. These results are similar to the disruptions observed in amphibian somites following heat shock. However, different parts of the segment pattern varied in their response; the head segments were very rarely affected, and disrupted regions rarely started in the middle abdomen (segments A5 and A6). The results are discussed in relation to two models (the clock and wavefront and progress zone models) that have been proposed as an explanation for the specification of the somite pattern in amphibians.


The risk of subsequent primary cancers after colorectal cancer in southeast England.
Multiple cancers may occur in an individual because of a genetic predisposition, environmental exposure, cancer therapy, or immunological deficiency. Colorectal cancer is one of the most commonly diagnosed cancers, and inherited factors play an important role in its aetiology. To characterise the occurrence of multiple primary cancers in patients diagnosed with colorectal cancer and explore the possibility of a common aetiology for different cancer sites. The Thames Cancer Registry database was used to identify patients with a first colorectal cancer, resident in the North or South Thames region, diagnosed between 1 January 1961 and 31 December 1995. A total of 127 281 patients were included, 61 433 men and 65 848 women. Observed numbers of cancers occurring after the diagnosis of colorectal cancer were compared with expected numbers, calculated using appropriate age, sex, and period specific rates, to obtain standardised incidence ratios. The occurrence of colorectal cancers subsequent to cancers at other sites was also examined. Small intestinal cancer was significantly increased in men diagnosed with colorectal cancer before the age of 60 years and in women diagnosed with colorectal cancer after the age of 65 years. Colorectal cancer was also significantly increased after a first diagnosis of cancer of the small intestine. Other cancer sites with a significant increase after colorectal cancer included the cervix uteri, corpus uteri, and ovary. Patients with colorectal cancer are at increased risk of developing cancer at a number of other sites. Some of these associations are consistent with the effects of known inherited cancer susceptibility genes.


True grit. One agency's story.
It's every home care agency's worst nightmare: the feds accuse you of fraud in Medicare and Medicaid billings. One agency refused to knuckle under--and managed to survive the ordeal with its integrity intact.


Expression of the Pseudomonas gene coding for carboxypeptidase G2 in Saccharomyces cerevisiae.
The Pseudomonas gene coding for carboxypeptidase G2 was introduced into Saccharomyces cerevisiae on an Escherichia coli/yeast shuttle vector pROG5. The level of enzyme activity obtained was independent of the orientation of the gene within the pBR322-derived tetracycline resistance gene of the vector, indicating that expression can occur from a Pseudomonas promoter in yeast.


Comparative transcriptomic analysis of human placentae at term and preterm delivery.
Preterm birth affects 1 out of every 10 infants in the United States, resulting in substantial neonatal morbidity and mortality. Currently, there are few predictive markers and few treatment options to prevent preterm birth. A healthy, functioning placenta is essential to positive pregnancy outcomes. Previous studies have suggested that placental pathology may play a role in preterm birth etiology. Therefore, we tested the hypothesis that preterm placentae may exhibit unique transcriptomic signatures compared to term samples reflective of their abnormal biology leading to this adverse outcome. We aggregated publicly available placental villous microarray data to generate a preterm and term sample dataset (n = 133, 55 preterm placentae and 78 normal term placentae). We identified differentially expressed genes using the linear regression for microarray (LIMMA) package and identified perturbations in known biological networks using Differential Rank Conservation (DIRAC). We identified 129 significantly differentially expressed genes between term and preterm placenta with 96 genes upregulated and 33 genes downregulated (P-value <0.05). Significant changes in gene expression in molecular networks related to Tumor Protein 53 and phosphatidylinositol signaling were identified using DIRAC. We have aggregated a uniformly normalized transcriptomic dataset and have identified novel and established genes and pathways associated with developmental regulation of the placenta and potential preterm birth pathology. These analyses provide a community resource to integrate with other high-dimensional datasets for additional insights in normal placental development and its disruption.


Clinical Question: In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes?
Answer: No. A randomized controlled trial of patients with heart failure and an ejection fraction > 45% showed that spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Level of Evidence for the Answer: A Limits: English, Adults, Randomized Controlled Trials, Meta-analysis, and Systematic review. Date Search Was Conducted: December 2015. Inclusion criteria: All randomized controlled trials, meta-analyses, and systematic reviews in patients with congestive heart failure with preserved ejection fractions, who were taking spironolactone, and published in the past 5 years. Exclusion criteria:; Age less than eighteen years, Eplerenone .


A study on nucleolar DNA: isolation of DNA from fibrillar components and ultrastructural localization of different DNA probes.
The nature and localization of DNA contained in the fibrillar centres and the dense fibrillar component (the fibrillar complex) in the nucleoli, was studied in human LEP cells, Sertoli cells, spermatogonia A and in mitotic chromosomes of stimulated lymphocytes. A novel procedure for isolating the intact fibrillar complex from LEP cells was used; the complex contains DNA that hybridizes to secondary constrictions of mitotic chromosomes and to 28 S rDNA sequences, on Southern blots. Electron microscopic DNA-DNA in situ hybridization was performed, with (a) a probe prepared from DNA extracted from the fibrillar complex of LEP cells, (b) a probe for human total genomic DNA, and (c) a probe for the transcribed part of human rDNA. On the basis of the results obtained we conclude that the ribosomal RNA genes in human Sertoli cells and spermatogonia A are predominantly associated with the dense fibrillar component, including the border region between fibrillar centres and the dense fibrillar component. The ribosomal RNA genes are the main, if not exclusive, DNA type present in the fibrillar complex in the studied cell types.


Detection of tumor contamination of peripheral stem cells in patients with lymphoma using cell culture and polymerase chain reaction technology.
The important question of whether residual tumor in the bone marrow or peripheral blood stem cell graft contributes to relapse in autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma can be addressed only if there is an accurate and sensitive measurement of tumor cell contamination of the graft. Assays utilizing DNA amplification based on the polymerase chain reaction (PCR) are highly sensitive. Tumor-specific primers and probes can be designed for the clonally rearranged Ig or T cell antigen receptor genes in the original tumors, and these can then be used to detect minimal residual disease in subsequent specimens. Specific translocations can also be exploited as tumor markers, and the t(14;18) translocation has been widely employed for detecting tumor cells in blood and bone marrow samples. Lymphoma cells have also been grown successfully in tissue culture, and the detection of tumor contamination of autologous grafts has been associated with a poorer prognosis in patients with intermediate- or high-grade lymphoma. It is of interest to compare the sensitivity of tumor detection and the predictive value for patient survival of the PCR-based and culture-based assays. The information obtained may help to determine whether minimal tumor contamination of an autologous graft is clinically significant and, if so, the assay(s) that should be employed.


Disrupted-in-schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first-episode psychosis.
The disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first-episode psychosis (FEP). Cerebrospinal fluid samples of patients with FEP (n = 50) and matched healthy controls (HCs; n = 47) were measured by the highly sensitive surface-based fluorescence intensity distribution analysis technology that enables single aggregate detection. We demonstrate that DISC1 protein aggregates are increased in cerebrospinal fluid samples of patients with FEP versus HCs. The concentration was in the low femtomolar range. No correlations were found with specific symptom levels, but the difference was particularly significant in the subset of patients with the diagnoses schizophrenia, unspecified (DSM-IV 295.9) or schizoaffective disorder (DSM-IV 295.70) at 18-month follow-up. DISC1 protein aggregate levels did not significantly change within the 18-month observation interval and were on average higher for individuals carrying the major DISC1 rs821577 allele, before correction. The occurrence of protein aggregates in vivo in patients with psychotic disorders has not been previously reported. It underscores the significance of posttranslational modifications of proteins both as pathogenetic mechanisms and as potential diagnostic markers in these disorders.


The G Protein-Coupled Receptor (GPR) 15 Counteracts Antibody-Mediated Skin Inflammation.
The G protein-coupled receptor 15 (GPR15) has recently been highlighted as an important regulator of T cell trafficking into the gut under physiological and pathophysiological conditions. Additionally, circumstantial evidence has accumulated that GPR15 may also play a role in the regulation of chronic inflammation. However, the (patho)physiological significance of GPR15 has, in general, remained rather enigmatic. In the present study, we have addressed the role of GPR15 in the effector phase of autoantibody-mediated skin inflammation, specifically in the antibody transfer mouse model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA). Subjecting Gpr15-/- mice to this model, we have uncovered that GPR15 counteracts skin inflammation. Thus, disease was markedly aggravated in Gpr15-/- mice, which was associated with an increased accumulation of γδ T cells in the dermis. Furthermore, GPR15L, the recently discovered cognate ligand of GPR15, was markedly upregulated in inflamed skin. Collectively, our results highlight GPR15 as counter-regulator of neutrophilic, antibody-mediated cutaneous inflammation. Enhancing the activity of GPR15 may therefore constitute a novel therapeutic principle in the treatment of pemphigoid diseases, such as BP-like EBA.


Cross-Cultural Differences and Psychometric Properties of the Japanese Actions and Feelings Questionnaire (J-AFQ).
Aims: We aimed to assess the psychometric properties of a Japanese version of the Actions and Feelings Questionnaire (J-AFQ), an 18-item self-report measure of non-verbal emotional communication, as well as to examine its transcultural properties. Methods: The J-AFQ was administered to 500 Japanese adults (age 20-49, 250 male), alongside the Japanese Broad Autism Phenotype Questionnaire (BAPQ-J) and Empathy Quotient (EQ-J). These were compared to a group of 597 British and Irish participants (age 16-18, 148 male). J-AFQ was assessed in terms of validity by confirmatory factor analysis and convergence with BAPQ-J and EQ-J using Pearson correlation. Internal consistency and differential item functioning (DIF) were assessed and compared between Japanese and UK/Irish participants. Results: Reversed worded items (RWIs) showed poor item-total correlations but excluding these left a 13-item version of the J-AFQ with good internal consistency and content validity. Consistent with the English version, J-AFQ scores correlated with EQ and lower BAPQ scores. However, comparing across cultures, J-AFQ scores were significantly lower in the Japanese sample, and there was evidence of important DIF by country in over half of the J-AFQ items Conclusion: Cultural differences in attitudes to self-report, as well as increased acquiescence to RWI's also seen in previous studies, limit the value of the 18-item instrument in Japanese culture. However, the 13-item J-AFQ is a valid and reliable measure of motor empathy, which, alongside the English version, offers promise for research in motor cognition and non-verbal emotional communication across cultures.


State of health of "non-respondents" in population studies of ischaemic heart disease in Moscow and Kaunas.
The authors analyse the results of medical examination of males aged 40-59 years in Moscow and Kaunas, divided into "respondents" and "non-respondents" in a population study of ischaemic heart disease. Among non-respondents, a higher incidence was found of such risk factors of ischaemic heart disease (IHD) as arterial hypertension, smoking, low physical activity and personality type A. On the other hand, hypercholesterolaemia was more frequent among respondents. Among non-respondents in Moscow as well as in Kaunas, there was a tendency towards a higher incidence of IHD and its clinical forms, and a higher proportion was treated over a longer period of time as out-patients or at hospital. The study proved the need to check the state of health of non-respondents in every mass screening of the population.


Comparison of image analysis with flow cytometry for DNA content analysis in pigmented lesions of the skin.
The DNA ploidy of 85 melanocytic skin lesions was determined by flow cytometry (FCM) and interactive image analysis (IA) using nuclear extracts of paraffin-embedded tissue. Of the 85 lesions analyzed, 43 were malignant melanomas in different stages of evolution, 15 were dysplastic nevi, 11 were Spitz nevi, and 16 were other types of nevi. Some of the last had features of congenital nevi. Within the melanoma category, there was 42% aneuploidy by FCM versus 56% by IA. Of those melanomas aneuploid by FCM, all but one were aneuploid by IA. All dysplastic nevi, 10/11 Spitz nevi and 15/16 other nevi were diploid by both methods. One of the 16 nevi from the "other types" category was tetraploid by IA but diploid by FCM. A single Spitz nevus was tetraploid by FCM but diploid by image analysis. While our results suggest that interactive IA is potentially a more sensitive method than FCM for detecting aneuploidy in cutaneous pigmented lesions, it remains to be shown whether this will translate into better prognostic assessment of the biologic behavior of melanocytic neoplasms than provided by flow cytometric ploidy analysis.


Identifying the electronic character and role of the Mn states in the valence band of (Ga,Mn)As.
We report high-resolution hard x-ray photoemission spectroscopy results on (Ga,Mn)As films as a function of Mn doping. Supported by theoretical calculations we identify, for both low (1%) and high (13%) Mn doping values, the electronic character of the states near the top of the valence band. Magnetization and temperature-dependent core-level photoemission spectra reveal how the delocalized character of the Mn states enables the bulk ferromagnetic properties of (Ga,Mn)As.


Expression and secretion of recombinant ovine beta-lactoglobulin in Saccharomyces cerevisiae and Kluyveromyces lactis.
High expression and secretion of recombinant ovine beta-lactoglobulin has been achieved in the yeast Kluyveromyces lactis. The yield of beta-lactoglobulin is 40-50 mg per litre of culture supernatant and accounts for approx. 72% of the total secreted protein. Constitutive expression is under the control of the Saccharomyces cerevisiae phosphoglycerate kinase promoter from an intronless version of the beta-lactoglobulin gene. Secretion is specified by the ovine protein's own signal sequence. this system, coupled to an efficient and novel recovery protocol, allows 30 mg of pure protein to be isolated from a typical 1 litre culture. The protein is virtually indistinguishable from beta-lactoglobulin conventionally purified from sheep milk by its behaviour in native PAGE and SDS/PAGE, reactivity to antibodies, CD, fluorescence spectroscopy and N-terminal sequencing. Attempts to achieve a similar expression and secretion system in the yeast S. cerevisiae met with only limited success, although it was found that heat-shock treatment modestly increased the yield up to approx. 3-4 mg per litre of culture supernatant. Site-directed mutagenesis showed that secretion in S. cerevisiae depended upon correct formation of the two disulphide bonds present in beta-lactoglobulin.


Measuring Frequency Fluctuations in Nonlinear Nanomechanical Resonators.
Advances in nanomechanics within recent years have demonstrated an always expanding range of devices, from top-down structures to appealing bottom-up MoS2 and graphene membranes, used for both sensing and component-oriented applications. One of the main concerns in all of these devices is frequency noise, which ultimately limits their applicability. This issue has attracted a lot of attention recently, and the origin of this noise remains elusive to date. In this article we present a very simple technique to measure frequency noise in nonlinear mechanical devices, based on the presence of bistability. It is illustrated on silicon-nitride high-stress doubly clamped beams, in a cryogenic environment. We report on the same T/ f dependence of the frequency noise power spectra as reported in the literature. But we also find unexpected damping fluctuations, amplified in the vicinity of the bifurcation points; this effect is clearly distinct from already reported nonlinear dephasing and poses a fundamental limit on the measurement of bifurcation frequencies. The technique is further applied to the measurement of frequency noise as a function of mode number, within the same device. The relative frequency noise for the fundamental flexure δ f/ f0 lies in the range 0.5-0.01 ppm (consistent with the literature for cryogenic MHz devices) and decreases with mode number in the range studied. The technique can be applied to any type of nanomechanical structure, enabling progress toward the understanding of intrinsic sources of noise in these devices.


Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy. First, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes. GR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p<0.001), CD4+ T cell (Phi=0.280, p<0.001), NK cell (Phi=0.280, p<0.001), macrophage (Phi=0.285, p<0.001), and dendritic cell (Phi=0.397, p<0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes. GR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.


[Medicine in Sardinia between XIXth and XXth century: Buggerru Mining Hospital].
In Italy, the town of Buggerru, Sardinia, could be considered the cradle of zinc extractive industries. Around Malfidano mine developed a mining village, that reached a population of 8000 inhabitants. It was a peculiar environment since the population included a lot of younger people, women and children workers. The extractive activity exposed all of them to health and life hazards. A hospital was founded in 1868, but was reorganized at the beginning of 20th century. Medical records enable to study the activity of Buggerru hospital, providing information on the complex health events of its inhabitants. For the history of public health and medicine, the events of these hospitals are a subject of interest, being the reflection of major episodes of those times.


Utilization of emergency center services by older adults with a psychiatric diagnosis.
Information regarding older adult emergency center (EC) patient characteristics remains limited, despite its increasing importance in health care delivery systems. This retrospective study encompasses all EC visits over an eight-year period (n = 825,682) to a large urban county hospital. Only participants with a primary psychiatric diagnosis were examined, and included a total of 53,894 adults, 18-64 years old and 1,478 adults, > or =65 years old. Despite an increasing aging population, EC visits for older adults with psychiatric disorders did not increase over time. Within the older adult sample, cognitive, psychotic, and bipolar disorders were associated with higher rates of admission to the hospital, while substance use, depressive, and anxiety disorders were associated with lower numbers of inpatient admissions. African-Americans were over-represented in the EC and admitted to the hospital at higher rates, compared to other ethnic groups. Caucasian patients were the group most frequently diagnosed with a substance use disorder. In conclusion, differences in race, and diagnosis support the idea that such variables directly relate to utilization rates, presentation, and disposition within the EC.


ATP conformations and ion binding modes in the active site of anthrax edema factor: a computational analysis.
The Edema Factor (EF), one of the virulence factors of anthrax, is an adenylyl cyclase that promotes the overproduction of cyclic-AMP (cAMP) from ATP, and therefore perturbs cell signaling. Crystallographic structures of EF bound to ATP analogs and reaction products, cyclic-AMP, and Pyrophosphate (PPi), revealed different substrate conformations and catalytic-cation binding modes, one or two cations being observed in the active site. To shed light into the biological significance of these crystallographic structures, the energetics, geometry, and dynamics of the active site are analyzed using molecular dynamics simulations. The ATP conformation observed in the one-metal-ion structure allows stronger interactions with the catalytic ion, and ATP is more restrained than in the structure containing two Mg(2+) ions. Therefore, we propose that the conformation observed in the one-ion crystal structure is a more probable starting point for the reaction. The simulations also suggest that a C3'-endo sugar pucker facilitates nucleophilic attack. Additionally, the two-cation binding mode restrains the mobility of the reaction products, and thus their tendency to dissociate.


Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker.
Autism is a neurodevelopmental disorder characterized by deficits in verbal communication, social interactions, and the presence of repetitive, stereotyped and compulsive behaviors. Excessive early brain growth is found commonly in some patients and may contribute to disease phenotype. Reports of increased levels of brain-derived neurotrophic factor (BDNF) and other neurotrophic-like factors in autistic neonates suggest that enhanced anabolic activity in CNS mediates this overgrowth effect. We have shown previously that in a subset of patients with severe autism and aggression, plasma levels of the secreted amyloid-β (Aβ) precursor protein-alpha form (sAPPα) were significantly elevated relative to controls and patients with mild-to-moderate autism. Here we further tested the hypothesis that levels of sAPPα and sAPPβ (proteolytic cleavage products of APP by α- and β-secretase, respectively) are deranged in autism and may contribute to an anabolic environment leading to brain overgrowth. We measured plasma levels of sAPPα, sAPPβ, Aβ peptides and BDNF by corresponding ELISA in a well characterized set of subjects. We included for analysis 18 control, 6 mild-to-moderate, and 15 severely autistic patient plasma samples. We have observed that sAPPα levels are increased and BDNF levels decreased in the plasma of patients with severe autism as compared to controls. Further, we show that Aβ1-40, Aβ1-42, and sAPPβ levels are significantly decreased in the plasma of patients with severe autism. These findings do not extend to patients with mild-to-moderate autism, providing a biochemical correlate of phenotypic severity. Taken together, this study provides evidence that sAPPα levels are generally elevated in severe autism and suggests that these patients may have aberrant non-amyloidogenic processing of APP.


Effect of heat treatment on the surface antigens of Haemophilus pleuropneumoniae.
Coagglutination and ring precipitation tests were used to study the effect of heat on the surface antigens of Haemophilus pleuropneumoniae strains employing the reference strains belonging to serotypes 1 to 7 and field isolates belonging to serotypes 1, 2, 3, 5, 6 and 7. By immunising rabbits with formalin-fixed whole-cell suspension, antibodies were obtained which sensitised Cowan I Staphylococcus aureus to coagglutinate antigen preparations which had not been heated, or heated at 56 degrees C, or boiled or autoclaved. Similar positive reactions were obtained with the ring precipitation test. Heating the cultures at 56 degrees C for one hour was best for exposing the most potent serotype-specific antigens in all the strains studied. All the reference strains and most of the field isolates possessed the thermostable type specific antigens which could withstand autoclaving for one hour. However, many field isolates belonging to serotype 1 did not possess this antigen. The apparent antigenic heterogeneity of serotype 1 strains based on the presence or absence of these thermostable antigens could be valuable in epidemiological investigations. It was shown that most potent serotype-specific antigens are present as freely diffusible material on the surface layer of the bacterial cells, which could easily be removed by washing in saline solution. Well washed bacterial cells devoid of surface materials are poor antigens. It is recommended that test strains should not be heated above 56 degrees C for serotyping because higher temperatures are liable to destroy the capsular antigen of some strains and render the culture untypeable.


A robust myoelectric pattern recognition using online sequential extreme learning machine for finger movement classification.
A robust myoelectric pattern-recognition-system requires a system that should work in the real application as good as in the laboratory. However, this demand should be handled properly and rigorously to achieve a robust myoelectric system. Electrode shift is an issue that usually emerges when dealing with robustness issue. In daily life, the placement of electrodes becomes a significant issue that can downgrade the performance of the system. This paper proposed a new way to overcome the robustness issue by conducting an update to the system to anticipate changes in the future such as electrode shift, improvement in muscle strength or any other issue. Such update will be used to generate an adaptation. The adaptation is done according to the user's need by employing an online sequential extreme learning (OS-ELM) to learn the training data chunk by chunk. OS-ELM enables the myoelectric system to learn from a small number of data to avoid cumbersome training process. The day-to-day experiment shows that the proposed system can maintain its performance on average accuracy around 85% whereas the non-adaptive system could not.


Functionally distinct high and low theta oscillations in the human hippocampus.
Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta's function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.


In vivo analysis of serotonin clearance in rat hippocampus reveals that repeated administration of p-methoxyamphetamine (PMA), but not 3,4-methylenedioxymethamphetamine (MDMA), leads to long-lasting deficits in serotonin transporter function.
p-Methoxyamphetamine (PMA) has been implicated in fatalities as a result of 'ecstasy' (MDMA) overdose worldwide. Like MDMA, acute effects are associated with marked changes in serotonergic neurotransmission, but the long-term effects of PMA are poorly understood. The aim of this study was to determine the effect of repeated PMA administration on in vitro measures of neurodegeneration: serotonin (5-HT) uptake, 5-HT transporter (SERT) density and 5-HT content in the hippocampus, and compare with effects on in vivo 5-HT clearance. Male rats received PMA, MDMA (4 or 15 mg/kg s.c., twice daily) or vehicle for 4 days and 2 weeks later indices of SERT function were measured. [(3)H]5-HT uptake into synaptosomes and [(3)H]cyanoimipramine binding to the SERT were significantly reduced by both PMA and MDMA treatments. 5-HT content was reduced in MDMA-, but not PMA-treatment. In contrast, clearance of locally applied 5-HT measured in vivo by chronoamperometry was only reduced in rats treated with 15 mg/kg PMA. The finding that 5-HT clearance in vivo was unaltered by MDMA treatment suggests that in vitro measures of 5-HT axonal degeneration do not necessarily predict potential compensatory mechanisms that maintain SERT function under basal conditions.