Creation of a "Wisconsin index" nomogram to predict the likelihood of additional hyperfunctioning parathyroid glands during parathyroidectomy.
The aim of our study was to create a preoperative "index" that could predict the likelihood of additional hyperfunctioning parathyroid glands and let the surgeon determine whether to wait for the intraoperative parathyroid hormone (ioPTH) or to explore further. During parathyroidectomy for primary hyperparathyroidism (PHPT), discovering a minimally "enlarged" parathyroid gland creates a dilemma for the surgeon regarding the need for further exploration. Although ioPTH testing can potentially solve this problem after a 20- to 30-minute period, several surgeons recognize that further operative exploration may be more effective. We analyzed a prospective database of 1235 consecutive patients who underwent parathyroidectomy for PHPT at our institution between March 2001 and August 2010. The Wisconsin Index (WIN) was defined as the multiplication of preoperative serum calcium by preoperative parathyroid hormone (PTH). Patients were divided into 3 WIN categories: low (<800), medium (801-1600), and high (>1600). The utility of the WIN was then validated on a subsequent cohort of 216 patients. The median age of the patients was 61 years (range, 10-91), and 77% of the patients were female. The mean preoperative calcium and PTH levels were 11.0 ± 0 mg/dL and 127 ± 3 pg/mL, respectively. The mean WIN for the entire cohort was 1461 ± 38 and highly correlated with gland weight (P < 0.000001). A single adenoma was identified in 1000 patients (81%), double adenoma in 100 patients (8%), and hyperplasia in 135 patients (11%). The mean gland weights for the 3 WIN catagories were low = 370 ± 33 mg, medium = 532 ± 39 mg, and high = 985 ± 28 mg, respectively (P < 0.000001). A WIN nomogram, consisting of the combination of WIN and parathyroid gland weight, accurately predicted the likelihood of additional hyperfunctioning parathyroid glands. For example, for a WIN of less than 800 and a gland weight of 500 mg, there is a 9% chance for additional hyperfunctioning parathyroid glands based on the WIN nomogram. In contrast, for the same gland weight, if the WIN is 801 to 1600, these chances increase to 28%, and if the WIN is more than 1600, the chance of multigland disease is 61%. Comparison between the predicted chances for another gland with the actual chance in the validation cohort identified an R(2) value of 0.96. The WIN nomogram predicts the likelihood of additional hyperfunctioning parathyroid glands during parathyroidectomy. This simple intraoperative tool may be used to guide the decision of whether to wait for ioPTH results or to proceed with further neck exploration.


Effect of dietary sesame oil as antioxidant on brain hippocampus of rat in focal cerebral ischemia.
Oxidative stress may be regarded as an imbalance between free radical production and opposing antioxidant defenses. Free radical oxidative stress is implicated in rat cerebral ischemia and naturaceutical antioxidants are dietary supplements that have been reported to have neuroprotective activity. Many studies have reported dietary sesame oil (SO) as an effective antioxidant. In the present study the neuroprotective effect of dietary SO was evaluated against middle cerebral artery occlusion (MCAO)-induced cerebral ischemia injury in rats. Rats were fed on diet (20% SO) for 15 days. The middle cerebral artery of adult male Wistar rat was occluded for 2 h and reperfused for 22 h. The antioxidant properties of brain were measured as levels of reduced glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS). A decrease in the activity of all the enzymatic and non-enzymatic antioxidants was observed along with an increase in lipid peroxidation (LPO) in MCAO group. The neurobehavioral activity of rats was also observed by using videopath analyzer. Dietary SO improved the antioxidant status in MCAO+SO group when compared with MCAO group. The results of neurobehavioral activity also support our biochemical data. The results obtained suggest protective effect of SO against cerebral ischemia in rat brain through their antioxidant properties.


Clinical relevance of verapamil plasma levels in stable angina pectoris.
Plasma levels of verapamil and norverapamil were evaluated in 77 patients who received oral verapamiL for treatment of angina pectoris. There was a sixfold interpatient variation in verapamil plasma concentrations, but plasma concentrations were linearly related to doses of the drug (240 to 480 mg/day) in the same patient (r = 0.81). Plasma concentrations of norverapamil, the major active metabolite of verapamil, were similar to those of verapamil. Although verapamil produced a significant improvement in exercise tolerance in most patients, the increase in exercise time was not related to plasma levels of the drug; however, most patients with improvement had plasma levels exceeding 100 ng/ml. An increase in the dose of verapamil from 320 to 480 mg daily produced a substantial (71%) increase in plasma levels of the drug but no significant increase in exercise tolerance (4%). The average increase in the P-R interval with 480 mg of verapamil in these 77 patients was small (8%) (161 +/- 18 to 174 +/- 22 ms); on.y six patients had first-degree heart block. These minor effects on atrioventricular conduction were noted despite plasma verapamil concentrations in 76 patients that exceeded 100 ng/ml, a level that successfully converts supraventricular tachycardias after intravenous drug administration. We differences between the effects of oral and intravenous verapamil on atrioventricular conduction may be the result of stereoselective hepatic inactivation of verapamil's I-isomer. Determination of plasma levels of verapamil is of limited value in the management of patients with angina pectoris, but may be useful in the identification of nonresponders with plasma levels less than 100 ng/ml who may benefit from a further increment in drug dose.


Impact of Aneurysm Multiplicity on Treatment and Outcome After Aneurysmal Subarachnoid Hemorrhage.
One-third of patients with aneurysmal subarachnoid hemorrhage (aSAH) have multiple intracranial aneurysms (MIA). To determine the predictors of outcome in aSAH patients with MIA compared to aSAH patients with a single intracranial aneurysm (SIA). The Swiss Study of Subarachnoid Hemorrhage dataset 2009-2014 was used to evaluate outcome in aSAH patients with MIA compared to patients with SIA with the aid of descriptive and multivariate regression analysis. The primary endpoints of this cohort study were presence of new stroke on computed tomography (CT) after aneurysm treatment, and presence of stroke on CT prior to discharge. The secondary endpoints were the clinical and the functional status, and the overall mortality at discharge and at 1 yr. Among 1689 consecutive patients, 467 had MIA (prevalence: 26.4%). The incidence of stroke was higher in the MIA than in the SIA group, both after aneurysm treatment (19.3% vs 15.1%) and at discharge (24% vs 21.4%). However, the 95% confidence interval (CI) for the corresponding odds ratio (OR) in our multivariate model included 1, indicating that the detected trends did not reach statistical significance. As for the secondary endpoints, aneurysm multiplicity was found to be an independent, statistically significant predictor for occurrence of a new focal neurological deficit between admission and discharge (OR 1.40, 95% CI 1.08-1.81). Yet, the MIA and SIA groups did not differ in terms of either functional outcome or overall survival. aSAH patients with MIA have a higher short-term morbidity than patients with SIA. This excess morbidity does not worsen the functional outcome or lower overall survival.


Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors.
During random screening of a small in-house library of compounds, certain substituted imidazo[1,2-a]pyridines were found to be weak allosteric inhibitors of HIV-1 reverse transcriptase (RT). A library of these compounds was prepared using the Groebke reaction and a subset of compounds prepared from 2-chlorobenzaldehyde, cyclohexyl isocyanide and a 6-substituted 2-aminopyridine showed good inhibitory activity in enzymatic (RT) and HIV anti-infectivity MAGI whole cell assays. The compound showing the best anti-HIV-1 IIIB whole cell activity (MAGI IC(50)=0.18 μM, IC(90)=1.06 μM), along with a good selectivity index (>800), was 2-(2-chlorophenyl)-3-(cyclohexylamino)imidazo[1,2-a]pyridine-5-carbonitrile 38.


Simultaneous electric production and sizing of emulsion droplets in microfluidics.
Microscale emulsions are widely used in fundamental and applied sciences. To expand their utilization, various methods have been developed for manipulating and measuring the physical properties of fabricated emulsions inside microchannels. Herein, we present an electric emulsification platform that can produce emulsions and simultaneously detect their physical properties (size and production speed). The characterization of the emulsion properties during the fabrication process will broaden the application fields for microscale emulsions because it can avoid time-consuming post image processing and simplify the emulsification platform. To accomplish this, a "bottleneck" channel is implanted between two reservoirs of immiscible fluids (continuous and dispersion phases). This channel can not only confine one fluid within the other when the electric field is on, resulting in emulsification via electrohydrodynamically induced Rayleigh instability, but also act as a resistive pulse sensor (RPS). The fluctuation of the liquid/liquid interface during emulsification induces the fluctuation of the electric resistance in the bottleneck channel, as the two fluid phases have different electrical conductivities. With this simple but dual-functional channel, the emulsion size (radius of 5-10 μm) and production speed (7-12 Hz) can be controlled by adjusting the electric field and the channel-neck geometry. Additionally, the properties can be measured using the RPS; the data obtained through the RPS exhibit high correlations with the validated data obtained using a high-speed camera and microscopy (>95%). The proposed buffer-less electric emulsification with the embedded RPS is a simple and cost-effective emulsion production method that allows real-time emulsion characterization with a limited sample volume.


Mortality results from the Göteborg randomised population-based prostate-cancer screening trial.
Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate. In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243. In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death. This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs. The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.


Regional specificity and practice: dynamic changes in object and spatial working memory.
Working memory (WM) tasks engage a network of brain regions that includes primary, unimodal, and multimodal associative cortices. Little is known, however, about whether task practice influences these types of regions differently. In this experiment, we used event-related fMRI to examine practice-related activation changes in different region types over the course of a scanning session while participants performed a delayed-recognition task. The task contained separate WM processing stages (encoding, maintenance, retrieval) and different materials (object, spatial), which allowed us to investigate the influence of practice on different component processes. We observed significant monotonic decreases, and not increases, in fMRI signal primarily in unimodal and multimodal regions. These decreases occurred during WM encoding and retrieval, but not during maintenance. Finally, regions specific to the type of memoranda (e.g., spatial or object) showed a lesser degree of sensitivity to practice as compared to regions activated by both types of memoranda, suggesting that these regions may be specialized more for carrying out processing within a particular modality than for experience-related flexibility. Overall, these findings indicate that task practice does not have a uniform effect on stages of WM processing, the type of WM memoranda being processed or on different types of brain regions. Instead, regions engaged during WM encoding and retrieval may have greater capacity for functional plasticity than WM maintenance. Additionally, the degree of specialization within brain regions may determine processing efficiency. Unimodal and multimodal regions that participate in both object and spatial processing may be specialized for flexible experience-related change, while those supporting primary sensorimotor processing may operate at optimal efficiency and are less susceptible to practice.


SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway.
Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.


A Cross-Species Gene Expression Marker-Based Genetic Map and QTL Analysis in Bambara Groundnut.
Bambara groundnut (Vigna subterranea (L.) Verdc.) is an underutilised legume crop, which has long been recognised as a protein-rich and drought-tolerant crop, used extensively in Sub-Saharan Africa. The aim of the study was to identify quantitative trait loci (QTL) involved in agronomic and drought-related traits using an expression marker-based genetic map based on major crop resources developed in soybean. The gene expression markers (GEMs) were generated at the (unmasked) probe-pair level after cross-hybridisation of bambara groundnut leaf RNA to the Affymetrix Soybean Genome GeneChip. A total of 753 markers grouped at an LOD (Logarithm of odds) of three, with 527 markers mapped into linkage groups. From this initial map, a spaced expression marker-based genetic map consisting of 13 linkage groups containing 218 GEMs, spanning 982.7 cM (centimorgan) of the bambara groundnut genome, was developed. Of the QTL detected, 46% were detected in both control and drought treatment populations, suggesting that they are the result of intrinsic trait differences between the parental lines used to construct the cross, with 31% detected in only one of the conditions. The present GEM map in bambara groundnut provides one technically feasible route for the translation of information and resources from major and model plant species to underutilised and resource-poor crops.


AAPM Task Group 264: The safe clinical implementation of MLC tracking in radiotherapy.
The era of real-time radiotherapy is upon us. Robotic and gimbaled linac tracking are clinically established technologies with the clinical realization of couch tracking in development. Multileaf collimators (MLCs) are a standard equipment for most cancer radiotherapy systems, and therefore MLC tracking is a potentially widely available technology. MLC tracking has been the subject of theoretical and experimental research for decades and was first implemented for patient treatments in 2013. The AAPM Task Group 264 Safe Clinical Implementation of MLC Tracking in Radiotherapy Report was charged to proactively provide the broader radiation oncology community with (a) clinical implementation guidelines including hardware, software, and clinical indications for use, (b) commissioning and quality assurance recommendations based on early user experience, as well as guidelines on Failure Mode and Effects Analysis, and (c) a discussion of potential future developments. The deliverables from this report include: an explanation of MLC tracking and its historical development; terms and definitions relevant to MLC tracking; the clinical benefit of, clinical experience with and clinical implementation guidelines for MLC tracking; quality assurance guidelines, including example quality assurance worksheets; a clinical decision pathway, future outlook and overall recommendations.


Three different approaches for the clarification of the interactions between lipoproteins and chondroitin-6-sulfate.
Two different experimental approaches were used for obtaining a comprehensive view and understanding of the interactions between apolipoprotein B-100 (ApoB-100) of low-density lipoprotein and apolipoprotein E (ApoE) of high-density lipoprotein and chondroitin-6-sulfate (C6S) of arterial proteoglycan. The techniques employed were partial filling affinity capillary electrophoresis (PF-ACE) and continuous flow quartz crystal microbalance (QCM). In addition, molecular dynamic (MD) simulations were used to provide a supportive visual insight into the interaction mechanism. A new tool for analysis of QCM-data was utilized, i.e., adsorption energy distribution calculations, which allowed a deeper understanding of the interactions, especially at different temperatures. The PF-ACE technique probed mainly the strong adsorption interactions whereas in the MD calculations short- and long-range interactions could be distinguished. Although there are differences in the techniques, a pretty good agreement was achieved between the three approaches for the interaction of 19 amino acid peptide of ApoB with C6S giving log affinity constants of 4.66 by QCM, 5.02 by PF-ACE, and 7.39 by MD, and for 15 amino acid peptide of ApoE with C6S 5.34 by QCM, 5.28 by PT-ACE, and 4.60 by MD at physiological temperature 37.0 °C.


Application of a MRI based index to longitudinal atrophy change in Alzheimer disease, mild cognitive impairment and healthy older individuals in the AddNeuroMed cohort.
Cross sectional studies of patients at risk of developing Alzheimer disease (AD) have identified several brain regions known to be prone to degeneration suitable as biomarkers, including hippocampal, ventricular, and whole brain volume. The aim of this study was to longitudinally evaluate an index based on morphometric measures derived from MRI data that could be used for classification of AD and healthy control subjects, as well as prediction of conversion from mild cognitive impairment (MCI) to AD. Patients originated from the AddNeuroMed project at baseline (119 AD, 119 MCI, 110 controls (CTL)) and 1-year follow-up (62 AD, 73 MCI, 79 CTL). Data consisted of 3D T1-weighted MR images, demographics, MMSE, ADAS-Cog, CERAD and CDR scores, and APOE e4 status. We computed an index using a multivariate classification model (AD vs. CTL), using orthogonal partial least squares to latent structures (OPLS). Sensitivity, specificity and AUC were determined. Performance of the classifier (AD vs. CTL) was high at baseline (10-fold cross-validation, 84% sensitivity, 91% specificity, 0.93 AUC) and at 1-year follow-up (92% sensitivity, 74% specificity, 0.93 AUC). Predictions of conversion from MCI to AD were good at baseline (77% of MCI converters) and at follow-up (91% of MCI converters). MCI carriers of the APOE e4 allele manifested more atrophy and presented a faster cognitive decline when compared to non-carriers. The derived index demonstrated a steady increase in atrophy over time, yielding higher accuracy in prediction at the time of clinical conversion. Neuropsychological tests appeared less sensitive to changes over time. However, taking the average of the two time points yielded better correlation between the index and cognitive scores as opposed to using cross-sectional data only. Thus, multivariate classification seemed to detect patterns of AD changes before conversion from MCI to AD and including longitudinal information is of great importance.


On the estimation of relative risk from vital statistical data.
A method is described for the determination of a measure of relative risk from vital statistical data. If the frequency of disease in a population is linearly related to the level of exposure to a given factor, then a measure of the relative risk can be estimated from the slope and intercept of the regression line. For example, when the exposure is measured in terms of the proportion of the population exposed to the factor, then the relative risk is equal to (Formula: see text). This offers an indirect but simple and inexpensive method for estimating relative risk. It should be used with caution, particularly where confounding factors may be responsible for the apparent association between disease and factor. Applications of the method to estimate the relative risk of (a) circulatory diseases in women using oral contraceptives and (b) ovarian cancer in women with different average family sizes, both yielded relative risk estimates comparable with those obtained from case-control and prospective studies.


Development of quantitative radioactive methodologies on paper to determine important lateral-flow immunoassay parameters.
The lateral-flow immunoassay (LFA) is a well-established diagnostic technology that has recently seen significant advancements due in part to the rapidly expanding fields of paper diagnostics and paper-fluidics. As LFA-based diagnostics become more complex, it becomes increasingly important to quantitatively determine important parameters during the design and evaluation process. However, current experimental methods for determining these parameters have certain limitations when applied to LFA systems. In this work, we describe our novel methods of combining paper and radioactive measurements to determine nanoprobe molarity, the number of antibodies per nanoprobe, and the forward and reverse rate constants for nanoprobe binding to immobilized target on the LFA test line. Using a model LFA system that detects for the presence of the protein transferrin (Tf), we demonstrate the application of our methods, which involve quantitative experimentation and mathematical modeling. We also compare the results of our rate constant experiments with traditional experiments to demonstrate how our methods more appropriately capture the influence of the LFA environment on the binding interaction. Our novel experimental approaches can therefore more efficiently guide the research process for LFA design, leading to more rapid advancement of the field of paper-based diagnostics.


Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review.
The authors compared the relative efficacy and safety of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) for the initial treatment of venous thromboembolism (VTE) between patients with and without cancer. By using Cochrane methodology for systematic reviews, separate meta-analyses were conducted for subgroups of patients with and without cancer, and relative risks (RRs) were compared for statistical significance. The methodologic quality for each outcome was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach. LMWH reduced mortality significantly compared with UFH in patients with cancer (RR of 0.71; 95% confidence interval [95% CI], 0.52-0.98 [moderate-quality evidence]) but not in patients without cancer (RR of 0.97; 95% CI, 0.65-1.46 [low-quality evidence]). However, the difference in the RR for the 2 subgroups did not reach statistical significance (P = .113). The difference between LMWH and UFH in the effect on recurrent VTE was not statistically significant in the subgroup with cancer (RR of 0.78; 95% CI, 0.29-2.08 [low-quality evidence]), in the subgroup without cancer (RR of 0.94; 95% CI, 0.60-1.46 [low-quality evidence]), or between the 2 subgroups (P = .367). No data were available for bleeding outcomes, thrombocytopenia, or postphlebitic syndrome. The current results indicated that LMWH most likely is superior to UFH in reducing mortality in the initial treatment of VTE for patients with cancer. There is a need for more and better designed trials to confirm these findings.


Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy.
Idiopathic inflammatory myopathies (IIM) involve chronic inflammation of skeletal muscle and subsequent muscle degeneration due to an uncontrolled autoimmune response; however, the mechanisms leading to pathogenesis are not well understood. A compromised sarcolemmal repair process could promote an aberrant exposure of intramuscular antigens with the subsequent initiation of an inflammatory response that contributes to IIM. Using an adoptive transfer mouse model of IIM, we show that sarcolemmal repair is significantly compromised in distal skeletal muscle in the absence of inflammation. We identified autoantibodies against TRIM72 (also known as MG53), a muscle-enriched membrane repair protein, in IIM patient sera and in our mouse model of IIM by ELISA. We found that patient sera with elevated levels of TRIM72 autoantibodies suppress sarcolemmal resealing in healthy skeletal muscle, and depletion of TRIM72 antibodies from these same serum samples rescues sarcolemmal repair capacity. Autoantibodies targeting TRIM72 lead to skeletal muscle fibers with compromised membrane barrier function, providing a continuous source of autoantigens to promote autoimmunity and further amplifying humoral responses. These findings reveal a potential pathogenic mechanism that acts as a feedback loop contributing to the progression of IIM.


Potential influence of selection criteria on the demographic composition of students in an Australian medical school.
Prior to 1999 students entering our MBBS course were selected on academic performance alone. We have now evaluated the impact on the demographics of subsequent cohorts of our standard entry students (those entering directly from high school) of the addition to the selection process of an aptitude test (UMAT), a highly structured interview and a rural incentive program. Students entering from 1985 to 1998, selected on academic performance alone (N = 1402), were compared to those from 1999 to 2011, selected on the basis of a combination of academic performance, interview score, and UMAT score together with the progressive introduction of a rural special entry pathway (N = 1437). Males decreased from 57% to 45% of the cohort, students of NE or SE Asian origin decreased from 30% to 13%, students born in Oceania increased from 52% to 69%, students of rural origin from 5% to 21% and those from independent high schools from 56% to 66%. The proportion of students from high schools with relative socio-educational disadvantage remained unchanged at approximately 10%. The changes reflect in part increasing numbers of female and independent high school applicants and the increasing rural quota. However, they were also associated with higher interview scores in females vs males and lower interview scores in those of NE and SE Asian origin compared to those born in Oceania or the UK. Total UMAT scores were unrelated to gender or region of origin. The revised selection processes had no impact on student representation from schools with relative socio-educational disadvantage. However, the introduction of special entry quotas for students of rural origin and a structured interview, but not an aptitude test, were associated with a change in gender balance and ethnicity of students in an Australian undergraduate MBBS course.


Automating curation using a natural language processing pipeline.
The tasks in BioCreative II were designed to approximate some of the laborious work involved in curating biomedical research papers. The approach to these tasks taken by the University of Edinburgh team was to adapt and extend the existing natural language processing (NLP) system that we have developed as part of a commercial curation assistant. Although this paper concentrates on using NLP to assist with curation, the system can be equally employed to extract types of information from the literature that is immediately relevant to biologists in general. Our system was among the highest performing on the interaction subtasks, and competitive performance on the gene mention task was achieved with minimal development effort. For the gene normalization task, a string matching technique that can be quickly applied to new domains was shown to perform close to average. The technologies being developed were shown to be readily adapted to the BioCreative II tasks. Although high performance may be obtained on individual tasks such as gene mention recognition and normalization, and document classification, tasks in which a number of components must be combined, such as detection and normalization of interacting protein pairs, are still challenging for NLP systems.


Dissociative electron attachment induced ring opening in five-membered heterocyclic compounds.
Five-membered heterocyclic structures, which exist widely in biological systems and play an active role in various biochemical processes, have been studied extensively from a fundamental perspective. Here, the fragmentation patterns of isoxazole, a representative five-membered heterocycle, upon dissociative electron attachment (DEA) were examined carefully by comparing isoxazole's products with those of its methylated derivatives. It was found that the most dominant DEA pathway occurs through the loss of hydrogen at C(3), which leads to ring opening by O-N bond cleavage at an energy of ∼1.5 eV. The ring opening was investigated further for DEA to other related five-membered ring compounds, i.e., oxazole and thiazole. The DEA-induced hydrogen loss was much less pronounced or quenched completely in these two compounds and simultaneous ring-opening behavior was not detected. This observation is of special interest to applied fields, for example, the pharmaceutical industry, because several drugs that contain isoxazole substructures exhibit extensive ring opening during biotransformation.


Unique Scopolamine Withdrawal Syndrome After Standard Transdermal Use.
We report the case of a 62-year-old woman who developed a withdrawal syndrome after using a standard 1.5-mg transdermal scopolamine (TDS) patch behind the ear to prevent motion sickness during sailing. The patient, who had used TDS occasionally for years without significant adverse effects, more recently, having worn a patch continuously for 7 days, approximately 24 to 36 hours after removing the patch developed dizziness, nausea, sweating, fatigue, and drowsiness. All symptoms disappeared without therapy in about 2 days. Approximately 1 year after the first episode, though, a very similar, more severe disabling reaction developed on 2 occasions. Drowsiness and malaise were accompanied by severe asthenia, orthostatic sweating, inability to stand, and hypotension. All clinical tests (electrocardiogram; spirometry; blood cell count; plasma levels of cortisol, sodium, and potassium; and liver and kidney function tests) were negative, and symptoms disappeared slowly, after several days. Although we are certain that scopolamine was responsible for the symptoms, we are less clear as to the nature of the disorder. The effects being more severe after a more prolonged use of the TDS patch, the increase in severity each successive time, and the time lag between removing the patch and appearance of symptoms all indicated a withdrawal syndrome for which several mechanisms may be suggested.


Total synthesis of anachelin H.
[structure: see text] The first total synthesis of anachelin H is reported. Starting from L-Ser, a stereodivergent synthesis of the polyketide fragment resulting in all possible diastereoisomers is described. The alkaloid peptide fragment is prepared via a tellurium-mediated oxidative aza annulation as the key step. Coupling of the fragments gave synthetic anachelin H, which was found to be identical to a sample of the natural product, thus confirming the configuration by total synthesis.


Bootstrap-based Feature Selection to Balance Model Discrimination and Predictor Significance: A Study of Stroke Prediction in Atrial Fibrillation.
Atrial fibrillation (AF) is a common cardiac arrhythmias, which increases the risk and severity of ischemic stroke. For predicting ischemic stroke in AF patients, a risk prediction model that can achieve both good model discrimination (e.g., A UC) and statistical significance ofpredictors is required in real clinical practices. In this paper, we propose a new bootstrap-based wrapper (Boots-wrapper) method of feature selection, and apply this method on Chinese Atrial Fibrillation Registry data to develop 1-year stroke prediction models in AF. The proposed method can heuristically search a subset of features to maximize the discrimination of the prediction model and minimize the penalty for the non-significant features. To achieve robust feature selection, we perform bootstrap sampling to get a more reliable estimate of the variation and significance statistics. The experimental results show that Boots-wrapper can balance model discrimination and statistical significance offeatures for developing AF stroke prediction models.


A Bayesian approach to retransformation bias in transformed regression.
Ecological data analysis often involves fitting linear or nonlinear equations to data after transforming either the response variable, the right side of the equation, or both, so that the standard suite of regression assumptions are more closely met. However, inference is usually done in the natural metric and it is well known that retransforming back to the original metric provides a biased estimator for the mean of the response variable. For the normal linear model, fit under a log-transformation, correction factors are available to reduce this bias, but these factors may not be generally applicable to all model forms or other transformations. We demonstrate that this problem is handled in a straightforward manner using a Bayesian approach, which is general for linear and nonlinear models and other transformations and model error structures. The Bayesian framework provides a predictive distribution for the response variable so that inference can be made at the mean, or over the entire distribution to incorporate the predictive uncertainty.


Multisensory integration: methodological approaches and emerging principles in the human brain.
Understanding the conditions under which the brain integrates the different sensory streams and the mechanisms supporting this phenomenon is now a question at the forefront of neuroscience. In this paper, we discuss the opportunities for investigating these multisensory processes using modern imaging techniques, the nature of the information obtainable from each method and their benefits and limitations. Despite considerable variability in terms of paradigm design and analysis, some consistent findings are beginning to emerge. The detection of brain activity in human neuroimaging studies that resembles multisensory integration responses at the cellular level in other species, suggests similar crossmodal binding mechanisms may be operational in the human brain. These mechanisms appear to be distributed across distinct neuronal networks that vary depending on the nature of the shared information between different sensory cues. For example, differing extents of correspondence in time, space or content seem to reliably bias the involvement of different integrative networks which code for these cues. A combination of data obtained from haemodynamic and electromagnetic methods, which offer high spatial or temporal resolution respectively, are providing converging evidence of multisensory interactions at both "early" and "late" stages of processing--suggesting a cascade of synergistic processes operating in parallel at different levels of the cortex.


Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies.
Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson's disease, tauopathies, Huntington's disease, and familial encephalopathy with neuroserpin inclusion bodies. The latter is an autosomal dominant disorder caused by point mutations in neuroserpin resulting in its destabilization. Mutant neuroserpin polymerizes and forms intracellular aggregates that eventually lead to neurodegeneration. We generated genetically modified mice expressing the late-onset S49P-Syracuse or the early-onset S52R-Portland mutation of neuroserpin in central nervous system neurons. Mice exhibited morphological, biochemical, and clinical features resembling those found in the human disease. Analysis of brains revealed large intraneuronal inclusions composed exclusively of mutant neuroserpin, accumulating long before the development of clinical symptoms in a time-dependent manner. Clinical symptoms and amount of neuroserpin inclusions correlated with the predicted instability of the protein. The presence of inclusion bodies in subclinical mice indicates that in humans the prevalence of the disease could be higher than anticipated. In addition to shedding light on the pathophysiology of the human disorder, these mice provide an excellent model to study mechanisms of neurodegeneration or establish novel therapies for familial encephalopathy with neuroserpin inclusion bodies and other neurodegenerative diseases with intracellular protein deposition.


Ranks of donor-recipient histocompatibility for human transplantation.
Correlation of leukocyte groups with skin and renal allograft survival indicates that ranks of histocompatibility based upon current genetic concepts of the HL-A system may provide an approach to the selection of optimally compatible subjects for clinical organ transplantation. Such ranks may be expressed as a net histocompatibility ratio (NHR) between prospective donors and recipients. The best clinical results have been when this ratio is of 0.5 to 1. Donor-recipient compatibility situations where the ratio was 0.25 or less have been associated with a high incidence of transplant failure, regardless of whether the organ source was a living, related donor or a cadaver donor.


Adhesive properties of Enterobacter sakazakii to human epithelial and brain microvascular endothelial cells.
Enterobacter sakazakii is an opportunistic pathogen that has been associated with sporadic cases and outbreaks causing meningitis, necrotizing enterocolitis and sepsis especially in neonates. However, up to now little is known about the mechanisms of pathogenicity in E. sakazakii. A necessary state in the successful colonization, establishment and ultimately production of disease by microbial pathogens is the ability to adhere to host surfaces such as mucous membranes, gastric and intestinal epithelial or endothelial tissue. This study examined for the first time the adherence ability of 50 E. sakazakii strains to the two epithelial cell lines HEp-2 and Caco-2, as well as the brain microvascular endothelial cell line HBMEC. Furthermore, the effects of bacterial culture conditions on the adherence behaviour were investigated. An attempt was made to characterize the factors involved in adherence. Two distinctive adherence patterns, a diffuse adhesion and the formation of localized clusters of bacteria on the cell surface could be distinguished on all three cell lines. In some strains, a mixture of both patterns was observed. Adherence was maximal during late exponential phase, and increased with higher MOI. The adhesion capacity of E. sakazakii to HBMEC cells was affected by the addition of blood to the bacteria growth medium. Mannose, hemagglutination, trypsin digestion experiments and transmission electron microscopy suggested that the adhesion of E. sakazakii to the epithelial and endothelial cells is mainly non-fimbrial based. Adherence experiments show heterogeneity within different E. sakazakii strains. In agreement with studies on E. cloacae, we found no relationship between the adhesive capacities in E. sakazakii and the eventual production of specific fimbriae. Further studies will have to be carried out in order to determine the adhesin(s) involved in the interaction of E. sakazakii with cells and to enhance knowledge of the pathogenesis of E. sakazakii infection.


A paradigm shift in brain research.
As late as the 1950s, it was assumed that communication between nerve cells in the brain occurred predominantly, if not entirely, by electrical impulses. A decade later, the theory of chemical transmission, which until then had been thought to occur only in the peripheral nervous system, had gained strong entrance for the central nervous system. This paradigm shift opened up an enormous new perspective in brain research, not least by facilitating the study of brain function by means of chemical tools, which in different ways could modify the chemical signaling between nerve cells. Moreover, such tools sometimes turned out to be useful as therapeutic agents. Thus for the first time, a variety of disorders in the central nervous system could be treated effectively.


Retrieval analyses of implanted biomaterials: light microscopic and scanning electron microscopic analyses of implants retrieved from humans.
We report analyses obtained from 135 implant cases retrieved from humans and submitted to the American Academy of Implant Dentistry Research Foundation--Medical College of Georgia Implant Retrieval Center. The undecalcified samples were embedded in polymethyl-methacrylate and examined with scanning electron microscopy and with routine light via polarized or Nomarski microscopy. Cases included both orthopedic and dental implants as well as entire mandibles obtained at autopsy. Significant numbers of submitted implants had substantial amounts of adhered bone, which permitted evaluation of human bone remodeling to osseointegrated implants. These implants failed because of implant fracture. As has been observed in animal studies, an interdigitating canaliculi network provided communication between interfacial osteocytes and osteocytes deeper within the remodeled osteonal and trabecular bone. Significant numbers of osseointegrated fractured hydroxyapatite-coated dental implants demonstrated the adequate serviceability of these implants prior to biomaterial fracture. In contrast, the hydroxyapatite coating was dissociated from retrieved orthopedic implants, leading to extensive cup loosening and case failure. Caution is advised for the use of hydroxyapatite-coated acetabular implants. This study therefore underscores the need for evaluation of failed human dental and orthopedic implants. Correlations can be drawn between human retrieval and experimental animal studies.


Distinct expression patterns of the immunogenic differentiation antigen NY-BR-1 in normal breast, testis and their malignant counterparts.
NY-BR-1 is a differentiation antigen and a potential target for cancer immunotherapy. Its mRNA expression is restricted to breast, testis, prostate and breast cancer by RT-PCR. In this study, we correlated NY-BR-1 protein and mRNA expression on tissue microarrays of mammary, prostatic and testicular malignancies using immunohistochemistry and in situ hybridization with probes for exon 4-7 and 30-33. NY-BR-1 mRNA was confined to primary spermatocytes, suggesting a role in spermatogenesis. Exon 4-7 and 30-33 were equally expressed this cell type. However, NY-BR-1 was absent in all germ cell tumours analyzed (n = 475) and present in one of 56 (2%) prostate carcinomas. In breast, NY-BR-1 mRNA expression was detected in 307 of 442 (70%) primary carcinomas, with strong correlation to its protein expression (p < 0.0001). mRNA expression was significantly stronger and more frequently detected by the exon 30-33 probe than by the exon 4-7 probe (70% vs. 35%, p < 0.0001), indicating the presence of alternative splice variants that lack 5-prime sequences. A similar restricted mRNA pattern was also observed in the normal breast epithelium. NY-BR-1 protein and mRNA correlated significantly with estrogen receptor alpha (ER alpha) protein expression (p < 0.0001), with stronger association to NY-BR-1 mRNA than protein (odds ratio 7.7 compared to 4.6). We identified 4 estrogen response elements (ERE)-like sequences nearby the promoter region, suggesting that NY-BR-1 transcription might be controlled by ER alpha. Accordingly, analysis of matching pairs of primary tumors with their recurrences showed a marked decrease of NY-BR-1 expression in recurrences after tamoxifen treatment (p < 0.0001).


Research activity and capacity in primary healthcare: the REACH study: a survey.
Despite increased investment in primary care research and development (R&D), the level of engagement of primary healthcare professionals with research remains poor. The aim of this study is to assess the level of research activity and capacity for research among primary healthcare professionals in a health authority of over one million people in a mixed urban/rural setting in the West of Ireland. A questionnaire, incorporating the R+D Culture Index, was sent to primary healthcare professionals in the HSE Western Region. Baseline characteristics were analysed with the use of one-way ANOVA and Chi-square test and the dependence of R&D Culture Index score on all sixteen available covariates was examined using multiple regression and regression tree modelling. There was a 54% response rate to the questionnaire. Primary healthcare professionals appeared to have an interest in and awareness of the importance of research in primary care but just 15% were found to be research active in this study. A more positive attitude towards an R&D culture was associated with having had previous research training, being currently involved in research and with not being a general practitioner (GP) (p < 0.001), but much variability in the R&D culture index score remained unexplained. Despite awareness of the importance of R&D in primary care and investment therein, primary healthcare professionals remain largely unengaged with the R&D process. This study highlights the issues that need to be addressed in order to encourage a shift towards a culture of R&D in primary care: lack of research training particularly in basic research skills and increased opportunities for research involvement. The use of the R&D Culture Index may enable groups to be identified that may be more research interested and can therefore be targeted in any future R&D strategy.


Species Delimitation and Description of Mesocriconema nebraskense n. sp. (Nematoda: Criconematidae), a Morphologically Cryptic, Parthenogenetic Species from North American Grasslands.
Nematode surveys of North American grasslands conducted from 2010 to 2015 frequently recovered a species of criconematid nematode morphologically resembling Mesocriconema curvatum. These specimens were recovered from remnant native prairies in the central tallgrass ecoregion of North America, and not from surrounding agroecosystems. Historical records indicate that M. curvatum is a cosmopolitan species feeding on a wide range of agronomic and native plants. DNA barcoding indicates North American grasslands contain at least 10 phylogenetically distinct lineages of Mesocriconema that resemble, but are not, M. curvatum. Analysis of the two most common lineages reveals two distinctly different population structures. The variation in population structure suggests unique evolutionary histories associated with their diversification. These two major lineages share a sympatric distribution and their slight morphological differences contrast with a high level of genetic separation. Based on their genetic divergence, fixed diagnostic nucleotides, population structure, species delimitation metrics, and a sympatric distribution, we believe that one of these distinct lineages warrants formal nomenclatural recognition. Herein, we provide formal recognition for Mesocriconema nebraskense n. sp. and discuss its relationship to other Mesocriconema lineages discovered in native North American grasslands.


Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist.
Numerous antagonists of tumor necrosis factor alpha (TNFalpha) have been developed to attenuate inflammation and accompanying pain in many disease processes. Soluble TNF receptor type II (sTNFRII) is one such antagonist that sequesters TNFalpha away from target receptors and attenuates its activity. Systemic delivery of soluble TNF receptors or other antagonists may have deleterious side effects associated with immune suppression, so that strategies for locally targeted drug delivery are of interest. Elastin-like polypeptides (ELPs) are biopolymers capable of in situ drug depot formation through thermally-driven supramolecular complexes at physiological temperatures. A recombinant fusion protein between ELP and sTNFRII was designed and evaluated for retention of bivalent functionality. Thermal sensitivity was observed by formation of supramolecular submicron-sized particles at 32 degrees C, with gradual resolubilization from the depot observed at physiological temperatures. In vitro refolding of the sTNFRII domain was required and the purified product exhibited an equilibrium dissociation constant for interacting with TNFalpha that was seven-fold higher than free sTNFRII. Furthermore, anti-TNF activity was observed in inhibiting TNFalpha-mediated cytotoxicity in the murine L929 fibrosarcoma assay. Potential advantages of this ELP-sTNFRII fusion protein as an anti-TNFa drug depot include facility of injection, in situ depot formation, low endotoxin content, and functionality against TNFalpha.


Metabolic bone disease in preterm infants.
Small preterm infants often develop osteopenia with or without rickets and with or without fractures. Whether these bone abnormalities all form part of the same disease process with a wide spectrum of presentation or whether each abnormality represents a different disease is as yet unclear. Bone mineralization depends largely on adequate supplies of calcium and phosphate. The normal intra-uterine accretion of these minerals is higher than can be achieved by feeding preterm babies postnatally with breastmilk or conventional formulas. Supplementation with calcium, phosphorus and vitamin D is needed to prevent the development of 'neonatal osteopathy'. The main action of vitamin D in the preterm baby is probably to increase the intestinal absorption of calcium and phosphorous, although it may, together with other calciotrophic hormones, have a more specific effect on bone growth.


Real-time quantitative expression studies of the zearalenone biosynthetic gene cluster in Fusarium graminearum.
The estrogenic mycotoxin zearalenone (ZON) produced by some Fusarium spp. causes reproductive problems and hyperestrogenic syndromes in mammals. In an effort to elucidate the molecular pathways of ZON production, we present a comparative real-time quantitative polymerase chain reaction expression study of seven contiguous genes in the ZON biosynthetic cluster on sterile rice and during wheat and oat infection. Under ZON production on rice, the polyketide synthase (PKS) genes PKS4 and PKS13, alcohol oxidase FG12056 gene, and transcriptional regulator FG02398 gene showed similarly upregulated patterns, whereas the nonribosomal peptide synthetase (NPS) FG02394, the K(+) channel beta subunit FG12015, and the protein kinase FG02399 displayed a variant pattern. During the same time period under wheat infection when no ZON was produced, the PKS genes and the NPS were downregulated relative to rice whereas the K(+) channel beta subunit gene FG12015 was markedly upregulated, suggesting that it may play a role in the infection process. This is the first expression study of ZON biosynthetic genes in planta. The results give insight into the regulation and activities of the ZON gene cluster under different experimental systems and suggest a connection between ZON and a K(+) channel that could reveal a novel function for ZON in Fusarium spp.


Independent factors associated with wearing different types of outdoor footwear in a representative inpatient population: a cross-sectional study.
Footwear can have both a positive and negative impact on lower limb health and mobility across the lifespan, influencing the risk of foot pain, ulceration, and falls in those at risk. Choice of footwear can be influenced by disease as well as sociocultural factors, yet few studies have investigated the types of footwear people wear and the profiles of those who wear them. The aim of this study was to investigate the prevalence and factors associated with outdoor footwear type worn most often in a representative inpatient population. This study was a secondary data analysis of a cohort of 733 inpatients that is highly representative of developed nations' hospitalised populations; 62 ± 19 years, 55.8% male, and 23.5% diabetes. Socio-demographic, medical history, peripheral arterial disease, peripheral neuropathy, foot deformity, foot ulcer history, amputation history and past foot treatment variables were collected. Participants selected the footwear type they mostly wore outside the house in the previous year from 16 types of footwear. Multivariate logistic regression identified independent factors associated with outdoor footwear types selected. The most common outdoor footwear types were: running shoes (20%), thongs/flip flops (14%), walking shoes (14%), sandals (13%) and boots (11%). Several socio-demographic, medical history and foot-related factors were independently associated (Odds Ratio; 95% Confidence Interval)) with different types of footwear. Running shoes were associated with male sex (2.7; 1.8-4.1); thongs with younger age (0.95 for each year; 0.94-0.97), being female (2.0; 1.2-3.1) and socio-economic status (3.1; 1.2-7.6); walking shoes with arthritis (1.9; 1.2-3.0); sandals with female sex (3.8; 2.3-6.2); boots with male sex (9.7; 4.3-21.6) and inner regional (2.6; 1.3-5.1) and remote (3.4; 1.2-9.5) residence (all, p < 0.05). We profiled the types of outdoor footwear worn most in a large diverse inpatient population and the factors associated with wearing them. Sex was the most consistent factor associated with outdoor footwear type. Females were more likely to wear thongs and sandals and males boots and running shoes. Overall, this data gives insights into the socio-demographic, medical and other health factors that are related to footwear choice in a large diverse population primarily of older age.


Conversion of a PI-anchored protein to an integral membrane protein by a single amino acid mutation.
Qa-2, a cell-surface glycoprotein anchored by phosphatidylinositol (PI), is structurally related to the class I transplantation antigens H-2 K, D, and L, which are integral membrane glycoproteins. The predicted transmembrane segment of Qa-2 differs from those of H-2 K, D, and L by the presence of an aspartate in place of a valine at position 295. A single base change that replaced this aspartate with valine resulted in cell-surface Qa-2 molecules that were insensitive to hydrolysis by a PI-specific phospholipase C and more resistant to papain cleavage, properties shared by H-2D. Cells expressing Asp----Val mutant Qa-2 proteins were still able to attach a PI anchor to endogenous proteins such as Thy-1 and J11D. It therefore appears that this single amino acid change converts Qa-2 from a PI-linked form into an integral membrane protein.


Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia.
Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8(+) T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T cells, might contribute to the increased risk of cancers as individuals age.


Internalizing and externalizing personality subtypes predict differences in functioning and outcomes among veterans in residential substance use disorder treatment.
There is a long history of using personality to subtype patients in treatment for substance use disorders (SUD). However, no one has validated a typology of SUD patients using a structural model of normal-range personality, particularly indicating whether subtypes differ on treatment processes and outcomes. We developed a personality-based typology among 196 military veterans enrolled in residential SUD treatment at a Veterans Affairs medical center. Patients were assessed at treatment entry, 1 month into treatment, and at discharge from treatment. Personality was assessed using the Multidimensional Personality Questionnaire-Brief Form at treatment entry. Latent profile analyses identified a 3-group solution consisting of low pathology, internalizing, and externalizing groups. The internalizing group scored lowest on measures of functioning at treatment entry, whereas the externalizing group scored more poorly on treatment processes and outcomes over the course of their residential stay (e.g., more stressful relationships with other residents, lower program alliance). These findings support a clinically meaningful typology of SUD patients based on a 3-factor model of personality and can serve as a guide for future efforts aimed at developing targeted interventions that can address the individual differences of patients in this population. (PsycINFO Database Record


Incidence of hepatitis C virus infection in Italian patients with idiopathic pulmonary fibrosis.
A viral cause of idiopathic pulmonary fibrosis (IPF) was recently suggested by a Japanese study in which a high prevalence of anti-hepatitis C virus (HCV) antibodies was detected. A subsequent British study failed to confirm these results. Antibodies to HCV were evaluated in 60 patients with IPF, 130 patients with non-interstitial lung disease, and in 4614 blood donors. HCV-RNA and HCV genotypes were evaluated in the anti-HCV positive patients with IPF. Anti-HCV antibodies were evaluated by ELISA and confirmed by recombinant immunoblotting assay (RIBA). HCV-RNA and genotypes were detected by reverse transcriptase polymerase chain reaction (PCR). Eight patients with IPF had anti-HCV antibodies detected by ELISA (13.3%). In the blood donor control group the prevalence of HCV antibodies was lower (0.3%). In patients with non-interstitial lung disease HCV antibody prevalence was 6.1%. In all eight patients with IPF found to be anti-HCV positive by ELISA, HCV antibodies were also detected by RIBA. Furthermore, all were HCV-RNA positive by PCR assay. HCV genotypes were identified in four of these eight patients. In all four genotype II was present and in two it was associated with genotype III and/or genotype IV. In the remaining four cases the genotype was not identified. Italian patients with IPF show an increased prevalence (approximately 13%) of HCV infection and viral replication, but the prevalence of anti-HCV antibodies does not differ from other lung diseases.


Running as a Key Lifestyle Medicine for Longevity.
Running is a popular and convenient leisure-time physical activity (PA) with a significant impact on longevity. In general, runners have a 25%-40% reduced risk of premature mortality and live approximately 3 years longer than non-runners. Recently, specific questions have emerged regarding the extent of the health benefits of running versus other types of PA, and perhaps more critically, whether there are diminishing returns on health and mortality outcomes with higher amounts of running. This review details the findings surrounding the impact of running on various health outcomes and premature mortality, highlights plausible underlying mechanisms linking running with chronic disease prevention and longevity, identifies the estimated additional life expectancy among runners and other active individuals, and discusses whether there is adequate evidence to suggest that longevity benefits are attenuated with higher doses of running.


Using HLA antibody detection, monitoring, and treatment to improve long-term allograft survival.
The evidence supporting HLA antibodies as a biomarker in transplant is substantial. It is becoming more clear that these patients represent a new phenotype of patient that is at the highest risk to rapidly progress to chronic damage. Therefore early detection of these high risk patients through serial screening is necessary. Additionally, once patients develop DSA positivity, IgG subclass testing may indicate how eminent his/her graft failure ensue. Moving forward, we should focus monitoring and treating at first detection of persistent antibodies. This may be the only reasonable way to have significant impact on long-term allograft survival.


Evaluating clinical decision support rules as an intervention in clinician workflows with technology.
The implementation of electronic health records in rural settings generated new challenges beyond those seen in urban hospitals. The preparation, implementation, and sustaining of clinical decision support rules require extensive attention to standards, content design, support resources, expert knowledge, and more. A formative evaluation was used to present progress and evolution of clinical decision support rule implementation and use within clinician workflows for application in an electronic health record. The rural hospital was able to use clinical decision support rules from five urban hospitals within its system to promote safety, prevent errors, establish evidence-based practices, and support communication. This article describes tools to validate initial 54 clinical decision support rules used in a rural referral hospital and 17 used in clinics. Since 2005, the study hospital has added specific system clinical decision support rules for catheter-acquired urinary tract infection, deep venous thrombosis, heart failure, and more. The findings validate the use of clinical decision support rules across sites and ability to use existing indicators to measure outcomes. Rural hospitals can rapidly overcome the barriers to prepare and implement as well as sustain use of clinical decision support rules with a systemized approach and support structures. A model for design and validation of clinical decision support rules into workflow processes is presented. The replication and reuse of clinical decision support rule templates with data specifications that follow data models can support reapplication of the rule intervention in subsequent rural and critical access hospitals through system support resources.


Alexithymia and the labeling of facial emotions: response slowing and increased motor and somatosensory processing.
Alexithymia is a personality trait that is characterized by difficulties in identifying and describing feelings. Previous studies have shown that alexithymia is related to problems in recognizing others' emotional facial expressions when these are presented with temporal constraints. These problems can be less severe when the expressions are visible for a relatively long time. Because the neural correlates of these recognition deficits are still relatively unexplored, we investigated the labeling of facial emotions and brain responses to facial emotions as a function of alexithymia. Forty-eight healthy participants had to label the emotional expression (angry, fearful, happy, or neutral) of faces presented for 1 or 3 seconds in a forced-choice format while undergoing functional magnetic resonance imaging. The participants' level of alexithymia was assessed using self-report and interview. In light of the previous findings, we focused our analysis on the alexithymia component of difficulties in describing feelings. Difficulties describing feelings, as assessed by the interview, were associated with increased reaction times for negative (i.e., angry and fearful) faces, but not with labeling accuracy. Moreover, individuals with higher alexithymia showed increased brain activation in the somatosensory cortex and supplementary motor area (SMA) in response to angry and fearful faces. These cortical areas are known to be involved in the simulation of the bodily (motor and somatosensory) components of facial emotions. The present data indicate that alexithymic individuals may use information related to bodily actions rather than affective states to understand the facial expressions of other persons.


Random perturbation: a potential aid in treatment of children with cerebral palsy.
The motor behaviour of children with cerebral palsy (CP) can be viewed in terms of a stable mode with very little flexibility that prevents adaptation to tasks. We hypothesized that the use of random perturbations (RP) would weaken excessive stability, introduce flexibility and enhance the effects of physical treatment. The objective was to evaluate the contribution of RP to gross motor function and mechanical efficiency (MEg) during intensive physiotherapy in children with CP. A convenience sample of 20 children with CP (mean age 8.2, range: 5.9-12.9 yrs) were matched by age and GMFCS level, and randomly assigned to structured intensive treatment (SIT) or to SIT + RP groups. Groups received one month of daily treatment. RP was applied by engine-induced random passive cycling for upper and lower limbs for up to 10 min in a 90-min treatment session. Gross Motor Function Measure (GMFM)-66 and gross mechanical efficiency (MEg) during stair climbing (MEg) were measured before and after treatment. GMFM-66 scores increased by about 1.0 in both groups. However, external work and MEg increased significantly more in SIT + RP than SIT. The increase in MEg in SIT + RP was independent of the level of motor function at baseline. The addition of RP in treatment of children with CP may have weakened previously established stereotypical motor patterns and introduced flexibility, thereby improving mechanical efficiency of a complex motor task. RP may enhance the effects of intensive treatment.


Vaccinations and multiple sclerosis.
Two problems must be considered in regard to the relationship between vaccinations and MS: Do vaccinations favour the first attack of MS? Do they increase the short- or long-term risk in patients with known disease? Answers to these questions are difficult due to the paucity of reported cases, our ignorance of the precise frequency of neurological adverse events in vaccines based on prospective studies, and finally by the lack of a well established pathophysiology. In most instances, the role of the vaccine is based on a temporal link between the injection and the onset of neurological disease, and more rarely to a positive reintroduction. Acute disseminated encephalomyelitis (ADEM), a monophasic and multifocal illness of the white and grey matter, has been observed following various viral or bacterial infections as well as vaccine injections for diseases such as pertussis, tetanus and yellow fever. The similarities between ADEM and experimental allergic encephalitis (EAE) are suggestive of an immunological process. In addition to the dramatic presentation of ADEM, more limited white matter involvement, such as optic neuritis or myelitis, has been reported following vaccine injections, and has occasionally been counted as the first attack of MS. In France, 25 million inhabitants, almost half of the population, were vaccinated against hepatitis B (HB) between 1991 and 1999. Several hundred cases of an acute central demyelinating event following HB vaccination were reported to the pharmacovigilance unit, leading to a modification of vaccination policy in the schools and the initiation of several studies designed to examine the possible relationship between the vaccine and the central demyelinating events. The results of these studies failed to establish the causality of the HB vaccine. Nevertheless, molecular mimicry between HB antigen(s) and one or more myelin proteins, or a non-specific activation of autoreactive lymphocytes, could constitute possible pathogenetic mechanisms for these adverse neurological events.


Distribution of the type III DNA methyltransferases modA, modB and modD among Neisseria meningitidis genotypes: implications for gene regulation and virulence.
Neisseria meningitidis is a human-specific bacterium that varies in invasive potential. All meningococci are carried in the nasopharynx, and most genotypes are very infrequently associated with invasive meningococcal disease; however, those belonging to the 'hyperinvasive lineages' are more frequently associated with sepsis or meningitis. Genome content is highly conserved between carriage and disease isolates, and differential gene expression has been proposed as a major determinant of the hyperinvasive phenotype. Three phase variable DNA methyltransferases (ModA, ModB and ModD), which mediate epigenetic regulation of distinct phase variable regulons (phasevarions), have been identified in N. meningitidis. Each mod gene has distinct alleles, defined by their Mod DNA recognition domain, and these target and methylate different DNA sequences, thereby regulating distinct gene sets. Here 211 meningococcal carriage and >1,400 disease isolates were surveyed for the distribution of meningococcal mod alleles. While modA11-12 and modB1-2 were found in most isolates, rarer alleles (e.g., modA15, modB4, modD1-6) were specific to particular genotypes as defined by clonal complex. This suggests that phase variable Mod proteins may be associated with distinct phenotypes and hence invasive potential of N. meningitidis strains.


Testosterone positively associated with both male mating effort and paternal behavior in Savanna baboons (Papio cynocephalus).
Testosterone (T) is often positively associated with male sexual behavior and negatively associated with paternal care. These associations have primarily been demonstrated in species where investment in paternal care begins well after mating activity is complete, when offspring are hatched or born. Different patterns may emerge in studies of species where investment in mating and paternal care overlap temporally, for instance in non-seasonal breeders in which males mate with multiple females sequentially and may simultaneously have multiple offspring of different ages. In a 9-year data set on levels of T in male baboons, fecal concentrations of T (fT) were positively associated with both mate guarding ("consortship") - a measure of current reproductive activity - and with the number of immature offspring a male had in his social group - a measure of past reproductive activity and an indicator of likely paternal behavior. To further examine the relationship between T and potential paternal behavior, we next drew on an intensive 8-month study of male behavior, and found that fathers were more likely to be in close proximity to their offspring than expected by chance. Because male baboons are known to provide paternal care, and because time in proximity to offspring would facilitate such care, this suggests that T concentrations in wild male baboons may be associated with both current reproductive activity and with current paternal behavior. These results are consistent with the predicted positive association between T and mating effort but not with a negative association between T and paternal care; in male baboons, high levels of T occur in males that are differentially associating with their offspring.


Management of type 2 diabetes mellitus by lifestyle, diet and medicinal plants.
Globally, the prevalence of chronic, noncommunicable diseases is increasing at an alarming rate and diabetes is one of them. If diabetes is not controlled then a lot of complication like coronary artery disease, cerebrovascular disease, peripheral vascular disease, retinopathy, nephropathy and neuropathy arise in diabetic patients and causes morbidity and/or mortality. Diabetes is increasing at an epidemic form and in near future the largest increases will take place in the regions dominated by developing economies. So, it will be a great social and economical burden to developing countries as well as the developed. But if we be aware about our diet and lifestyle and take proper medication we may prevent and reduce the prevalence of diabetes. Oral medicine plays an important role in management of diabetes. But most of the oral drugs are costly and have a lot of side effects. For this it is also necessary to take medicines with fewer or no side effects. And antidiabetic medicinal plants may play an important role in this case. In this article we have tried to describe how diet and lifestyle with using medicinal plants may help to prevent or maintain diabetes and help to reduce the mortality and morbidity due to diabetes or complication related to it.


Dynamics of Mycobacterium tuberculosis Ag85B Revealed by a Sensitive Enzyme-Linked Immunosorbent Assay.
Secretion of specific proteins contributes to pathogenesis and immune responses in tuberculosis and other bacterial infections, yet the kinetics of protein secretion and fate of secreted proteins in vivo are poorly understood. We generated new monoclonal antibodies that recognize the Mycobacteriumtuberculosis secreted protein Ag85B and used them to establish and characterize a sensitive enzyme-linked immunosorbent assay (ELISA) to quantitate Ag85B in samples generated in vitro and in vivo We found that nutritional or culture conditions had little impact on the secretion of Ag85B and that there is considerable variation in Ag85B secretion by distinct strains in the M. tuberculosis complex: compared with the commonly used H37Rv strain (lineage 4), Mycobacteriumafricanum (lineage 6) secretes less Ag85B, and two strains from lineage 2 secrete more Ag85B. We also used the ELISA to determine that the rate of secretion of Ag85B is 10- to 100-fold lower than that of proteins secreted by Gram-negative and Gram-positive bacteria, respectively. ELISA quantitation of Ag85B in lung homogenates of M. tuberculosis H37Rv-infected mice revealed that although Ag85B accumulates in the lungs as the bacterial population expands, the amount of Ag85B per bacterium decreases nearly 10,000-fold at later stages of infection, coincident with the development of T cell responses and arrest of bacterial population growth. These results indicate that bacterial protein secretion in vivo is dynamic and regulated, and quantitation of secreted bacterial proteins can contribute to the understanding of pathogenesis and immunity in tuberculosis and other infections.IMPORTANCE Bacterial protein secretion contributes to host-pathogen interactions, yet the process and consequences of bacterial protein secretion during infection are poorly understood. We developed a sensitive ELISA to quantitate a protein (termed Ag85B) secreted by M. tuberculosis and used it to find that Ag85B secretion occurs with slower kinetics than for proteins secreted by Gram-positive and Gram-negative bacteria and that accumulation of Ag85B in the lungs is markedly regulated as a function of the bacterial population density. Our results demonstrate that quantitation of bacterial proteins during infection can reveal novel insights into host-pathogen interactions.


Headache prevalence and characteristics among adolescents in the general population: a comparison between retrospect questionnaire and prospective paper diary data.
In the present school-based study, a convenience sample of 237 adolescents in grade 6-9 and second year in high school (age 12-18 years) was recruited from a city and a smaller town. The aim of the study was to compare information on the prevalence and various characteristics of headaches not related to disease in a retrospect questionnaire and prospective daily recordings of headaches in a standard paper diary during a 3-week period. Besides headache severity, number of headache days, intensity levels and duration of headache episodes were estimated with both assessment methods. Most of the school children suffered from tension-type headaches and a smaller portion of migraine attacks. The overall results showed that school children significantly (p < 0.001) overestimated headache intensity in questionnaires as compared to diary recordings, whereas they underestimated frequency (p < 0.001) and duration (p < 0.001) of headaches. While the correlations on headache severity, frequency and duration between retrospect information in questionnaires and prospective diary recordings were low, the agreement varied with levels of headache characteristics. Our findings concur well with results from a few similar community studies on headache complaints in school-aged children. We recommend that prospective recordings in diaries should be systematically used in clinical practice but also in epidemiological surveys to increase the validity and reliability in estimates of point prevalence of headache complaints in children and adolescents.


The effect of protein content of the diet on the rate of urea formation in sheep liver.
1. In the livers of six sheep given a high-protein diet, the concentrations of certain urea-cycle enzymes [ornithine transcarbamoylase, arginine synthetase (combined activity of argininosuccinate synthetase and argininosuccinase) and arginase] were significantly greater than when the sheep were given a low-protein diet. Alkaline phosphatase activity/mg. of liver protein was not significantly affected by diet. 2. Three sheep previously given the high-protein diet showed no significant rise in the concentration of ammonia in the blood after the administration of urea (0.5g./kg. body wt.). The concentration of ammonia in the blood of the three sheep given the low-protein diet rose exponentially with time after dosing with urea and all sheep died. 3. It is suggested that tolerance to ammonia toxicity in the sheep is at least partly a function of the activity of the urea-cycle enzymes in the liver.


Pension plan participation among married couples.
We present descriptive statistics on pension participation and types of pensions among married couples, using data from the 1996/2008 Panels of the Survey of Income and Program Participation and Social Security administrative records. Previous research has focused on pension coverage by marital status, but has not examined couples as a unit. Because couples usually share income, viewing them as a unit provides a better picture of potential access to income from retirement plans. Our analysis compares 1998 and 2009 data because substantial changes occurred in the pension landscape over this decade that could have influenced the prevalence of different pension plans, although we observe modest changes in participation rates and types of plans over the period. We find that in 20 percent of couples, neither spouse participated in a pension plan; in 10 percent, the wife was the only participant; and in 37 percent, the husband was the only participant.


Trends in endocrinology related research articles in a medical journal from India.
The details about the research productivity in the specialty of endocrinology from India is lacking. We plan to assess the publishing trends and the research productivity of Endocrinology related research articles published in the Journal of the Association of Physicians of India (JAPI). We carried the bibliometric analysis of endocrinology related articles from JAPI. The data were obtained from the JAPI website for the publications between 2000 and 2011. The articles were analyzed for the type (original article, case reports, correspondence, and pictorial image), subspecialty (diabetes, thyroid, etc.), and place of the research. Data were presented with descriptive statistics in numbers and percentages. Out of a total 2977 articles published by JAPI, 312 articles belong to endocrine subspecialty. Endocrinology related articles constitute about 11.2%-23.2% of the published articles per year in JAPI and the percentage is increasing every year. Original articles (52%) and case reports (27%) constituite the majority, while the rest were letters to editor (9%) and pictorial images (12%). Diabetes (57%) and metabolic bone disorders (16%) lead the subspecialty articles, followed by thyroid (9%), adrenal and gonad (8%), and pituitary (8%). Chennai (20%), Mumbai (14%), and Delhi (9%) are the top 3 places contributing to the articles followed by Chandigarh and Varanasi. Majority of endocrinology related research productivity is seen in form of original articles and case reports. Diabetes is the leading disease with maximum research articles from Chennai and other glands are equally represented in the research productivity.


Novel cancer therapy targeting microbiome.
In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.


Tob1 is expressed in developing and adult gonads and is associated with the P-body marker, Dcp2.
Tob1 is a member of the BTG/TOB family of proteins with established antiproliferative function. In Danio rerio and Xenopus laevis, the Tob1 gene is expressed from the one-cell stage through to early gastrula stages, followed in later development by discrete expression in many tissues including the notochord and somites. In both mouse and human, Tob1 is expressed in many adult tissues including the testis and ovary; however, the specific cell types are unknown. We examine Tob1 gene expression in mouse in developing germ cells and in sorted male germ cells (gonocytes, spermatogonia, pachytene spermatocytes and round spermatids) by reverse transcription and droplet digital polymerase chain reaction (RT-ddPCR) and in adult ovary and testis by immunofluorescence with anti-Tob1 protein staining. By RT-ddPCR, Tob1 expression was low in developing male germ cells but was highly expressed in round spermatids. In developing female germ cells undergoing entry into meiosis, it increased 10-fold. Tob1 was also highly expressed in round spermatids and in oocytes in all stages of folliculogenesis. Notably, a marker for P-bodies, Dcp-2, was also highly expressed in round spermatids and all oocyte stages examined. The cytoplasmic presence of Tob1 protein in round spermatids and oocytes and the association of Tob1 protein with Dcp2 in both cell types suggest that Tob1 protein plays a role in post-transcriptional mechanisms.


Deep Learning-Based Cell Detection and Extraction in Thin Blood Smears for Malaria Diagnosis.
Malaria is a major health threat caused by Plasmodium parasites that infect the red blood cells. Two predominant types of Plasmodium parasites are Plasmodium vivax (P. vivax) and Plasmodium falciparum (P. falciparum). Diagnosis of malaria typically involves visual microscopy examination of blood smears for malaria parasites. This is a tedious, error-prone visual inspection task requiring microscopy expertise which is often lacking in resource-poor settings. To address these problems, attempts have been made in recent years to automate malaria diagnosis using machine learning approaches. Several challenges need to be met for a machine learning approach to be successful in malaria diagnosis. Microscopy images acquired at different sites often vary in color, contrast, and consistency caused by different smear preparation and staining methods. Moreover, touching and overlapping cells complicate the red blood cell detection process, which can lead to inaccurate blood cell counts and thus incorrect parasitemia calculations. In this work, we propose a red blood cell detection and extraction framework to enable processing and analysis of single cells for follow-up processes like counting infected cells or identifying parasite species in thin blood smears. This framework consists of two modules: a cell detection module and a cell extraction module. The cell detection module trains a modified Channel-wise Feature Pyramid Network for Medicine (CFPNet-M) deep learning network that takes the green channel of the image and the color-deconvolution processed image as inputs, and learns a truncated distance transform image of cell annotations. CFPNet-M is chosen due to its low resource requirements, while the distance transform allows achieving more accurate cell counts for dense cells. Once the cells are detected by the network, the cell extraction module is used to extract single cells from the original image and count the number of cells. Our preliminary results based on 193 patients (including 148 P. Falciparum infected patients, and 45 uninfected patients) show that our framework achieves cell count accuracy of 92.2%.


Mutations of intermediate effect are responsible for adaptation in evolving Pseudomonas fluorescens populations.
The fixation of a beneficial mutation represents the first step in adaptation, and the average effect of such mutations is therefore a fundamental property of evolving populations. It is nevertheless poorly characterized because the rarity of beneficial mutations makes it difficult to obtain reliable estimates of fitness. We obtained 68 genotypes each containing a single fixed beneficial mutation from experimental populations of Pseudomonas fluorescens, evolving in medium with serine as the sole carbon source and estimated the selective advantage of each by competition with the ancestor. The distribution of selection coefficients is modal and closely resembles the Weibull distribution. The average selection coefficient (2.1) and beneficial mutation rate (3.8x10(-8)) are high relative to previous studies, possibly because the ancestral population grows poorly in serine-limited medium. Our experiment suggests that the initial stages of adaptation to stressful environments will involve the substitution of mutations with large effect on fitness.


Radioimmunoassay of plasma equilin and estrone in postmenopausal women after the administration of premarin.
A RIA for the measurement of plasma equilin (3-hydroxy-1,3,5-(10)7-estratetraen-17-one) and estrone in postmenopausal women and other estrogen-deficient women on exogenous equine estrogen replacement therapy is described. Antiserum against estriol-3,16,17-trihemisuccinate-HSA and high specific activity [2,4-3H]equilin and [6,7-3H]estrone were used in the assay procedure. Specificity of the assay was achieved by separation of equilin from estrone by chromatography on micro-Celite partition columns using silver nitrate as the stationary phase. The sensitivity of the standard curves for both equilin and estrone was 10-20 pg, and the smallest amount of estrone and equilin that could be measured accurately in the plasma was 250 pg/ml for both steroids. The coefficient of variation for both steroids ranged from 1-8%, over a range of 250-5000 pg/ml plasma. The interassay coefficients of variation for equilin and estrone were 4.6% and 2.4%, respectively. After the administration of 10 mg Premarin iv, maximum concentrations of 4 and 11.2 ng/ml for equilin and estrone, respectively, were obtained after 20 min. Thereafter, both steroids disappeared from the plasma gradually. When 10 mg Premarin were administered orally, equilin and estrone appeared in the blood gradually, and maximum levels of 560 and 1400 pg/ml were reached after 3 and 5 h for equilin and estrone, respectively. Equilin gradually disappeared, and by 24 h, only small amounts (125 pg/ml) were detectable. The levels of estrone declined more rapidly, though it was still detectable after 24 h. These preliminary results indicate that equilin sulfate is converted to circulating unconjugated equilin in a manner similar to the conversion of circulating estrone sulfate to estrone.


Computed tomographic appearance of primary lung tumors in dogs.
Canine primary lung tumors typically appear radiographically as a well-circumscribed solitary mass in the periphery of a caudal lung lobe. Consolidated and diffuse forms of primary lung tumors have also been described. Nineteen dogs with computed tomographic (CT) images of the thorax and a histological diagnosis of primary lung tumor (17 primary carcinomas and two primary sarcomas) were evaluated retrospectively to characterize the CT findings. All primary lung tumors were bronchocentric in origin with internal air bronchograms. The bronchi were typically narrowed, displaced, and often obstructed by the tumor. Eighteen of 19 (95%) of the tumors were solitary and there was one pneumonic/alveolar form. Most solitary tumors were well circumscribed (17/18), located in the central to periphery of the lung (14/18), and in a cranial or caudal lobe (16/19). Most primary lung tumors (11/17) had mild to moderate heterogeneous contrast enhancement. Five of 19 dogs (26%) had evidence of pulmonary metastasis. Internal mineralization (3/19) and tracheobronchial lymphadenopathy (4/19) were also identified. On CT examination, solitary, well circumscribed, bronchocentric masses with internal air bronchograms are consistent with a primary pulmonary tumor in dogs.


Impaired short-term memory for pitch in congenital amusia.
Congenital amusia is a neuro-developmental disorder of music perception and production. The hypothesis is that the musical deficits arise from altered pitch processing, with impairments in pitch discrimination (i.e., pitch change detection, pitch direction discrimination and identification) and short-term memory. The present review article focuses on the deficit of short-term memory for pitch. Overall, the data discussed here suggest impairments at each level of processing in short-term memory tasks; starting with the encoding of the pitch information and the creation of the adequate memory trace, the retention of the pitch traces over time as well as the recollection and comparison of the stored information with newly incoming information. These impairments have been related to altered brain responses in a distributed fronto-temporal network, associated with decreased connectivity between these structures, as well as in abnormalities in the connectivity between the two auditory cortices. In contrast, amusic participants׳ short-term memory abilities for verbal material are preserved. These findings show that short-term memory deficits in congenital amusia are specific to pitch, suggesting a pitch-memory system that is, at least partly, separated from verbal memory. This article is part of a Special Issue entitled SI: Auditory working memory.


Biochemical investigation of human tumours in vivo with phosphorus-31 magnetic resonance spectroscopy.
The bioenergetic state of 15 human tumours was examined with phosphorus-31 magnetic resonance spectroscopy. A striking diversity in metabolic patterns was observed, and significant differences from normal tissue were seen in all cases. A common feature was an elevation of intracellular pH, which may be related to an increase in Na+/H+ exchange during cell activation. It is unlikely that the patterns observed directly correlate with malignancy, but characterisation of the energetic state of a given tumour in a given physiological environment may help in the design and evaluation of interventions for that specific case.


Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system.
A cytotoxic effect of human neutrophils on mammalian tumor cells is demonstrated. Cytotoxicity depends on the presence of intact neutrophils, phagocytosable particles, and a halide cofactor and is inhibited by azide, cyanide, and catalase. Neutrophils from patients with myeloperoxidase (MPO) deficiency or defective H1O2 production are not cytotoxic, but activity is resotred by addition of purified MPO or H2O2 respectively. The findings support a mechanism involving the phagocytosis-induced extracellular release of MPO and H2O2 and their reation with a halide cofactor to damage the target cells.


Burrowing and nest building behavior as indicators of well-being in mice.
The assessment of pain, distress and suffering, as well as evaluation of the efficacy of stress-reduction strategies, is crucial in animal experimentation but can be challenging in laboratory mice. Nest building and burrowing performance, observed in the home cage, have proved to be valuable and easy-to-use tools to assess brain damage or malfunction as well as neurodegenerative diseases. Both behaviors are used as parameters in models of psychiatric disorders or to monitor sickness behavior following infection. Their use has been proposed in more realistic and clinically relevant preclinical models of disease, and reduction of these behaviors seems to be especially useful as an early sign of dysfunction and to monitor disease progression. Finally, both behaviors are reduced by pain and stress. Therefore, in combination with specific disease markers, changes in nest building and burrowing performance may help provide a global picture of a mouse's state, and thus aid monitoring to ensure well-being in animal experimentation.