Clinical characteristics of an apparent life-threatening event (ALTE) and the subsequent occurrence of prolonged apnea or prolonged bradycardia.
The objective of this study was to test the hypothesis that the characteristics of an apparent life-threatening event (ALTE) influence the risk for a subsequent episode of prolonged apnea or bradycardia. Data were obtained from 182 infants referred because of an apparent life-threatening event who were followed up at home for 2 lunar months on an apnea/bradycardia monitor with recording capability. A prolonged episode was defined as apnea > or = 20 sec long or an episode of bradycardia > or = 10 sec in duration as validated and measured from the event recordings. Seventeen percent of infants had at least one episode of prolonged apnea or prolonged bradycardia. Change in skin color, degree of resuscitative intervention, and behavioral state were not statistically significant factors influencing the risk of a subsequent prolonged episode. Contrary to clinical expectation, a significantly greater percentage of infants subsequently had a prolonged episode whose muscle tone was described as normal during the ALTE (24.0%), when compared with those infants whose ALTE was associated with limpness or increased muscle tone (9.3%). The coexistence of gastroesophageal reflux did not influence the overall results. The observations in this study place in question the clinical approach of relying on the detailed characteristics of an ALTE in determining the need for follow-up studies and/or home monitoring.


Calcitonin gene-related peptide receptor inhibition reduces neuronal activity induced by prolonged increase in nitric oxide in the rat spinal trigeminal nucleus.
Infusion of nitric oxide (NO) donors is known to induce delayed attacks of migraine and cluster headache or aggravate tension-type headaches in patients suffering from these primary headaches. Previously we have reported that infusion of NO donors in the rat causes delayed neuronal activity in the spinal trigeminal nucleus, which parallels the above clinical observations. Suggesting that endogenous NO production is involved in the generation of primary headaches, we used this animal model of meningeal nociception to determine whether a prolonged increase in NO levels causes an increase in neuronal activity. In anaesthetized rats spinal trigeminal neurons with afferent input from the exposed dura were recorded. Continuous intravenous infusion of the NO donors sodium nitroprusside (25 microg/kg/h) or glycerol trinitrate (250 microg/kg/h) for 2 h induced a persisting increase in neuronal activity but no change in systemic blood pressure. In this activated trigeminal system the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS (900 microg/kg) was infused. Spinal trigeminal activity was significantly reduced within minutes and to a similar extent as previously reported in animals not treated with NO. Slow continuous NO infusion may be a model of the active headache phase, and inhibition of CGRP receptors can reverse the induced neuronal activity.


Cloning, sequencing and expression analysis of a novel gene BR-1 that is expressed in normal human brain tissue but not in glioma tumor samples.
Using the technique of differential hybridization of a human fetal brain library, we identified a novel gene, brain 1 (BR-1). This gene is expressed in normal brain but has low or no expression in human gliomas. We have cloned and sequenced the full-length cDNA corresponding to this gene. A data base search for the nucleotide sequence homology was performed for BR-1. The BR-1 sequence showed strong homology to a human genomic clone from chromosome 2. Moderate sequence homology was observed between BR-1 and an expressed sequence tag (EST) from a human placenta library. Three different regions of BR-1 also showed homology to a mouse EST that is similar to EL-10 gene. Sequence analysis indicated that the protein sequence for BR-1 has one tyrosine kinase phosphorylation site and two N-myristoylation sites. Northern blot analysis indicated that the BR-1 gene is expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas. A low level of expression of BR-1 is observed in the cerebellum, cerebral cortex, spinal cord, occipital lobe and putamen. The BR-1 gene is also expressed in fetal brain, liver and kidney. Low expression of BR-1 gene was observed in a number of non-brain tumor cell lines. RT-PCR analysis indicated that the BR-1 gene was expressed in non-neoplastic (epilepsy specimens) but not in six oligodendrogliomas and three oligoastrocytoma tumor samples analyzed. BR-1 was not expressed in either seven low grade gliomas or eight grade IV glioblastoma tumor tissue samples analyzed. Three glioblastoma cell lines did show low expression of the BR-1 gene. On the basis of its expression properties, we conclude that BR-1 is a potential novel tumor suppressor gene.


Direct tracing of NH3 and N2O emissions associated with urea fertilization approaches, using static incubation cells.
Nitrogen fertilization contributes significantly to crop production globally. However, low efficiency application management approaches lead to substantial N losses of which ammonia and nitrous oxide are known as environmental threats. Urea, the largest N fertilization source globally, is associated with high ammonia losses. A large variety of application modes are practiced under different environmental conditions worldwide. Yet, the complexity of N-processes in different soils, under changing agro-environmental conditions, challenges the evaluation of fertilization approaches efficiency in reducing N-gaseous losses. In this research a simply designed static incubation cell was connected to a Long-Path gas cell and a Fourier Transform IR spectrometer (LP-FTIR), allowing online determination of ammonia and nitrous oxide emissions in parallel to tracking mineral N-dynamics in soil samples. The static chamber was used to evaluate different application approaches of urea (i.e., incorporation or surface application with or without wetting) in a Sandy Loam and to compare surface applied regular urea vs. urea amended with the urease inhibitors NPPT+NBPT [N-(n-butyl) thiophosphoric triamide and N-(n-propyl) thiophosphoric triamide, respectively] in four different representative soils. Ammonia emissions peaked few days after application, where highest losses were observed for surface application mode. Highest emissions, up to 5% (w/w) of applied Urea-N, were obtained with the lighter and more basic soils (Sandy Loam and Loess; pH > 7.9). Nitrous oxide emissions showed a lag period of ~1 week and were higher under lower urea application rates, and when nitrification was faster (~1-1.3% (w/w) of applied N). Urease inhibitors significantly reduced ammonia losses in all tested soils and particularly in the Sandy Loam and Loess. Their effect on nitrous oxide losses were observed with the Sandy Loam and particularly after 2 weeks. The static system may underestimate realistic ammonia losses, but it offers a rather simply operated system, providing information about N-gaseous losses for improving N-fertilization management.


Architecture of models for prebiotic synthesis of nucleic acids: template-directed synthesis of oligoguanylates using N-cyanoimidazole.
N-Cyanoimidazole is an efficient condensing agent for the polymerization of guanosine 5'-phosphate (pG) on a poly(C) template in an aqueous solution. At 0 degree C, up to about 30% of input pG was converted to a mixture of oligomers with a mean chain length of up to 7. The effect of divalent metal ions in the polymerization of pG on a poly(C) template was not so considerable as in that of oligo(A) on a poly(U) template. In the polymerization of pG, the moderate yields were obtaind in the presence of Co2+, Ni2+ and Cu2+.


Fibrous histiocytoma of the larynx.
We present a case of fibrous histiocytoma of the larynx in a young female who presented eight years ago and is still alive and well with no evidence of any regional invasion or distant metastasis. This rare lesion has been described in 30 cases previously of which 26 were malignant and four benign. Our case is unusual in a sense that histologically it has not been possible to determine its exact biological behaviour and growth potential. However, clinically it behaved as a low-grade malignant tumour.


Postsynaptic NO/cGMP increases NMDA receptor currents via hyperpolarization-activated cyclic nucleotide-gated channels in the hippocampus.
The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO-GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg(2+) increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg(2+). In sum, our data indicate that postsynaptic cGMP increases the N-methyl-D-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP.


Validity of a portable glucose, total cholesterol, and triglycerides multi-analyzer in adults.
This study investigated the accuracy and precision of the Accutrend Plus system to determine blood glucose, total cholesterol, and plasma triglycerides in adults and evaluated its efficiency in measuring these blood variables. The sample consisted of 53 subjects (≥ 18 years). For blood variable laboratory determination, venous blood samples were collected and processed in a Labmax 240 analyzer. To measure blood variables with the Accutrend Plus system, samples of capillary blood were collected. In the analysis, the following tests were included: Wilcoxon and Student's t-tests for paired samples, Lin's concordance coefficient, Bland-Altman method, receiver operating characteristic curve, McNemar test, and k statistics. The results show that the Accutrend Plus system provided significantly higher values (p ≤ .05) of glucose and triglycerides but not of total cholesterol (p > .05) as compared to the values determined in the laboratory. However, the system showed good reproducibility (Lin's coefficient: glucose = .958, triglycerides = .992, total cholesterol = .940) and high concordance with the laboratory method (Lin's coefficient: glucose = .952, triglycerides = .990, total cholesterol = .944) and high sensitivity (glucose = 80.0%, triglycerides = 90.5%, total cholesterol = 84.4%) and specificity (glucose = 100.0%, triglycerides = 96.9%, total cholesterol = 95.2%) in the discrimination of high values of the three blood variables analyzed. It could be concluded that despite the tendency to overestimate glucose and triglyceride levels, a portable multi-analyzer is a valid alternative for the monitoring of metabolic disorders and cardiovascular risk factors.


Profiling spontaneous speech decline in Alzheimer's disease: a longitudinal study.
This study aims to document the nature and progression of spontaneous speech impairment suffered by patients with Alzheimer's disease (AD) over a 12-month period, using both cross-sectional and prospective longitudinal design. Thirty one mild-moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex oral description task at baseline. The AD patients then underwent follow-up assessments at 6 and 12 months. Cross-sectional comparisons indicated that mild-moderate AD patients produced more word-finding delays (WFDs) and empty and indefinite phrases, while producing fewer pictorial themes, repairing fewer errors, responding to fewer WFDs, produce shorter and less complex phrases and produce speech with less intonational contour than controls. However, the two groups could not be distinguished on the basis of phonological paraphasias. Longitudinal follow-up, however, suggested that phonological processing deteriorates over time, where the prevalence of phonological errors increased over 12 months. Discussion Consistent with findings from neuropsychological, neuropathological and neuroimaging studies, the language deterioration shown by the AD patients shows a pattern of impairment dominated by semantic errors, which is later joined by a disruption in the phonological aspects of speech.


Structural and dynamic characterization of intrinsically disordered human securin by NMR spectroscopy.
Understanding the molecular action of securin, the inhibitor of separase in mitosis, is of immense theoretical and biomedical importance. The residue-level structural description of an intrinsically disordered protein of this length (202 amino acids, containing 24 prolines), however, represents a particular challenge. Here we combined (1)H-detected and (13)C-detected protonless NMR experiments to achieve full assignment of securin's backbone amide resonances. Chemical shifts, (15)N relaxation rates (R(1), R(2), (1)H-(15)N NOEs), (1)H exchange rates with the solvent (CLEANEX-PM), and (1)H-(15)N residual dipolar couplings were determined along the entire length of the protein. This analysis showed that securin is not entirely disordered, but segregates into a largely disordered N-terminal half and a C-terminal half with transient segmental order, within which the segment D(150)-F(159) has a significant helical tendency and segments E(113)-S(127) and W(174)-L(178) also show a significant deviation from random-coil behavior. These results, in combination with bioinformatic and biochemical data on the securin/separase interaction, shed light on the inhibitory action of securin on separase.


LC/MS/MS of steroids having vicinal diol as electrospray-active boronates.
A derivatization procedure with (3-dimethylaminophenyl)dihydroxyborane (DAPB) was introduced to enhance the detectability of steroids having a vicinal diol in LC/electrospray ionization (ESI)-MS/MS. DAPB reacted with the vicinal diol on the steroids [4β-hydroxycholesterol (4-HCh), pregnanetriol (PT) and 20R,22R-dihydroxycholesterol] in pyridine at 50°C within 1 h. The resulting DAPB-derivatives were highly responsive in ESI-MS operating in the positive-ion mode and gave characteristic product ions during MS/MS, which enabled sensitive detection using a selected reaction monitoring mode; the detection responses of the DAPB-derivatives were increased by 20-160-fold over those of the intact steroids and the limits of detection were in the low femtomole or attomole range. The derivatization procedure was successfully applied to biological sample analysis; the derivatization followed by LC/ESI-MS/MS enabled the specific detection of trace amounts of 4-HCh in human plasma and PT in human urine with a small sample volume, simple pretreatment and short chromatographic run time.


Chronic exposure to environmental stressors enhances production of natural and specific antibodies in rats.
Although the immunosuppressive effect of chronic stress has been established, a stress response that downregulates the whole immune system does not make biological sense, especially if an animal has to endure difficult times in which there is also increased infection risk. At high animal densities, animals are faced simultaneously with food restriction (FR), social conflict (SC), and greater parasite-pathogen exposure. We hypothesized that the stress response to chronic stressors that covary with infection risk is not entirely immunosuppressive. Our prediction was that a chronically stressed animal would respond by enhancing innate defenses, while reducing investment in acquired immunity. In a laboratory setting, rats were exposed to prolonged FR and/or SC, and natural and specific antibody levels were repeatedly measured. Our prediction was fulfilled only partly, as FR and SC interacted to enhance natural antibodies, but rats exposed to either or both stressors also showed significantly higher levels of specific antibodies. These results suggest that, in the rat, chronic stress results in a prioritization of both innate and acquired humoral defenses, which makes biological sense provided the stressors examined usually signal an increased infection risk.


Lobeline shows protective effects against MPTP-induced dopaminergic neuron death and attenuates behavior deficits in animals.
We previously demonstrated that lobeline effectively inhibited dopamine transporter (DAT)-mediated dopamine (DA) transportation. Therefore, the present study aimed to investigate whether lobeline shows protective effects against neurotoxin-induced cell death in vivo. Mice were administered 30 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and treated with 80 mg/kg L-dopa, 10 mg/kg GBR12935 or 1 or 3 mg/kg lobeline, respectively, via injection. Rotarod and swim tests as well as tyrosine hydroxylase (TH) immunohistochemistry were carried out to evaluate the effects of these drugs. Compared with L-DA and GBR12935, lobeline (3 mg/kg administered via intraperitoneal injection) on behavior and dopaminergic neurons. Compared with L-DA and GBR12935, lobeline (3 mg/kg injected subcutaneously) significantly reduced MPTP induced locomotive deficits detected in behavioral tests. In addition, TH immunostaining showed that lobeline (3 mg/kg) markedly decreased the neurotoxin-induced immunoreactivity loss in the substantia nigra and striatum. Lobeline may be useful in the protection of dopaminergic neurons and may alleviate the symptoms of Parkinson's disease.


Development and Internal Validation of a Prediction Model to Estimate the Probability of Needing Aggressive Immunosuppressive Therapy With Cytostatics in de Novo Lupus Nephritis Patients.
To develop a multivariable clinical prediction model for the requirement of aggressive immunosuppression with cytostatics, based on simple clinical record data and lab tests. The model is defined in accordance with the result of the kidney biopsies. Retrospective study conducted with data from patients 16 years and older, with SLE and nephritis with less than 6 months of evolution. An initial bivariate analysis was conducted to select the variables to be included in a multiple logistic regression model. Goodness of fit was evaluated using a Hosmer-Lemeshow test (H-L) and the discrimination capacity of the model by means of the area under the ROC (AUC) curve. Data from 242 patients was gathered; of these, 18.2% (n=44) did not need an addition of cytostatics according to the findings of their kidney biopsies. The variables included in the final model were 24-h proteinuria, diastolic blood pressure, creatinine, C3 complement and the interaction of hematuria with leukocyturia in urinary sediment. The model showed excellent discrimination (AUC=0.929; 95% CI=0.894-0.963) and adequate calibration (H-L, P=.959). In recent-onset LN patients, the decision to use or not to use intensive immunosuppressive therapy could be performed based on our prediction model as an alternative to kidney biopsies.


The elevated lipoprotein-associated phospholipase A2 activity is associated with the occurrence and recurrence of acute cerebral infarction.
There is a strong association between lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and atherosclerosis-related diseases. The aim of this study was to investigate the role of Lp-PLA2 in the ischemic stroke and further offer clinical evidence that measuring Lp-PLA2 helps predict the risk of stroke occurrence and recurrence. A total of 328 hospitalized patients were recruited, including 179 cases of acute cerebral infarction (ACI) and 149 non-ACI controls. The serum level of Lp-PLA2 in ACI was significantly higher than non-ACI. The serum level of Lp-PLA2 in the recurrence of ACI was significantly higher than the nonrecurrence. The serum levels of Lp-PLA2 in large-artery atherosclerosis subtype were the highest among the subtypes of the Trial of Org 10172 in Acute Stroke Treatment and non-ACI controls. The level of Lp-PLA2 in large-artery atherosclerosis and the cardioembolism group was statistically significantly higher than that of the control cases. There was no statistically significant difference between the small-vessel occlusion group and the control cases. The present study confirmed that the elevated Lp-PLA2 level can be a risk factor for ischemic stroke in the Chinese population. The serum level of Lp-PLA2 may be a predictive factor for the recurrence of ACI.


Ecology of Problem Individuals and the Efficacy of Selective Wildlife Management.
As a result of ecological and social drivers, the management of problems caused by wildlife is becoming more selective, often targeting specific animals. Narrowing the sights of management relies upon the ecology of certain 'problem individuals' and their disproportionate contribution to impacts upon human interests. We assess the ecological evidence for problem individuals and confirm that some individuals or classes can be both disproportionately responsible and more likely to reoffend. The benefits of management can sometimes be short-lived, and selective management can affect tolerance of wildlife for better or worse, but, when effectively targeted, selective management can bring benefits by mitigating impact and conflict, often in a more socially acceptable way.


The Graphics System for the 80's.
Forty years ago, the first General Purpose Raster Graphics Processor made the transition from research project to commercial product. This is the story of the creation of a new graphics system and the startup company that produced it in the early days of raster computer graphics.


Dipeptidyl peptidase III of human cataractous lenses. Partial purification.
A partial purification of dipeptidyl peptidase III has been achieved from human cataractous lens. The specific activity was increased 45.5-fold over that of the original aqueous extract. The exopeptidase exhibited a marked preference for the release of Arg-Arg from Arg-Arg-2-NNap at the optimum pH 8.8 and 37 degrees. The Km for this substrate was estimated to be 6.061 X 10(-3). Lens DPP III was inhibited by EDTA, p-chloromercuriphenyl sulfonate, puromycin and DFP. The preparation contained leucyl aminopeptidase and a neutral endopeptidase as contaminating proteases.


Photosynthetic capacity of senescent leaves for a subtropical broadleaf deciduous tree species Liquidambar formosana Hance.
Photosynthetic capacity and leaf life span generally determine how much carbon a plant assimilates during the growing season. Leaves of deciduous tree species start senescence in late season, but whether the senescent leaves still retain capacity of carbon assimilation remains a question. In this study, we investigated leaf phenology and photosynthesis of a subtropical broadleaf deciduous tree species Liquidambar formosana Hance in the central southern continental China. The results show that L. formosana has extended leaf senescence (more than 2 months) with a substantial number of red leaves persisting on the tree. Leaf photosynthetic capacity decreases over season, but the senescent red leaves still maintain relatively high photosynthetic capacity at 42%, 66% and 66% of the mature leaves for net photosynthesis rate, apparent quantum yield, and quantum yield at the light compensation point, respectively. These results indicate that L. formosana may still contribute to carbon sink during leaf senescence.


[Research progress on regulated necrosis in acute kidney injury].
Regulated necrosis is a newly discovered new cell death pathway, including necroptosis, pyroptosis and ferroptosis. It has been reported to play a key role in acute kidney injury (AKI) induced by ischemia/reperfusion, cisplatin and other drugs, and rhabdomyolysis. Studying the role of regulated necrosis-related pathways in AKI is expected to provide a new direction for clarifying the pathogenesis and treatment of AKI, with potential therapy and application prospects. In this review, we summarize the related signaling pathways of necroptosis, pyroptosis and ferroptosis, and the related research progress in AKI, in order to provide potential targets for the prevention and treatment of AKI.


New perspectives in patient education for cardiac surgery using 3D-printing and virtual reality.
Preoperative anxiety in cardiac surgery can lead to prolonged hospital stays and negative postoperative outcomes. An improved patient education using 3D models may reduce preoperative anxiety and risks associated with it. Patient education was performed with standardized paper-based methods (n = 34), 3D-printed models (n = 34) or virtual reality models (n = 31). Anxiety and procedural understanding were evaluated using questionnaires prior to and after the patient education. Additionally, time spent for the education and overall quality were evaluated among further basic characteristics (age, gender, medical expertise, previous non-cardiac surgery and previously informed patients). Included surgeries were coronary artery bypass graft, surgical aortic valve replacement and thoracic aortic aneurysm surgery. A significant reduction in anxiety measured by Visual Analog Scale was achieved after patient education with virtual reality models (5.00 to 4.32, Δ-0.68, p < 0.001). Procedural knowledge significantly increased for every group after the patient education while the visualization and satisfaction were best rated for patient education with virtual reality. Patients rated the quality of the patient education using both visualization methods individually [3D and virtual reality (VR) models] higher compared to the control group of conventional paper-sheets (control paper-sheets: 86.32 ± 11.89%, 3D: 94.12 ± 9.25%, p < 0.0095, VR: 92.90 ± 11.01%, p < 0.0412). Routine patient education with additional 3D models can significantly improve the patients' satisfaction and reduce subjective preoperative anxiety effectively.


Providing a web-based online medical record with electronic communication capabilities to patients with congestive heart failure: randomized trial.
It is possible to provide patients with secure access to their medical records using the Internet. Such access may assist patients in the self-management of chronic diseases such as heart failure. To assess how a patient-accessible online medical record affects patient care and clinic operations. The SPPARO (System Providing Access to Records Online) software consisted of a web-based electronic medical record, an educational guide, and a messaging system enabling electronic communication between the patient and staff. A randomized controlled trial was conducted in a specialty practice for patients with heart failure. Surveys assessing doctor-patient communication, adherence, and health status were conducted at baseline, 6 months, and 1 year. Use of the system, message volume, utilization of clinical services, and mortality were monitored. One hundred and seven patients were enrolled (54 intervention and 53 controls). At 12 months, the intervention group was not found to be superior in self-efficacy (KCCQ self-efficacy score 91 vs. 85, p=0.08), but was superior in general adherence (MOS compliance score 85 vs. 78, p=0.01). A trend was observed for better satisfaction with doctor-patient communication. The intervention group had more emergency department visits (20 vs. 8, p=0.03), but these visits were not temporally related to use of the online medical record. There were no adverse effects from use of the system. Providing patients with congestive heart failure access to an online medical record was feasible and improved adherence. An effect on health status could not be demonstrated in this pilot study.


Organ culture stability of the intervertebral disc: rat versus rabbit.
There is a need to develop mechanically active culture systems to better understand the role of mechanical stresses in intervertebral disc (IVD) degeneration. Motion segment cultures that preserve the native IVD structure and adjacent vertebral bodies are preferred as model systems, but rapid ex vivo tissue degeneration limits their usefulness. The stability of rat and rabbit IVDs is of particular interest, as their small size makes them otherwise suitable for motion segment culture. The goal of this study was to determine if there are substantial differences in the susceptibility of rat and rabbit IVDs to culture-induced degeneration. Lumbar IVD motion segments were harvested from young adult male Sprague-Dawley rats and New Zealand White rabbits and cultured under standard conditions for 14 days. Biochemical assays and safranin-O histology showed that while glycosaminoglycan (GAG) loss was minimal in rabbit IVDs, it was progressive and severe in rat IVDs. In the rat IVD, GAG loss was concomitant with the loss of notochordal cells and the migration of endplate (EP) cells into the nucleus pulposus (NP). None of these changes were evident in the rabbit IVDs. Compared to rabbit IVDs, rat IVDs also showed increased matrix metalloproteinase-3 (MMP-3) and sharply decreased collagen type I and II collagen expression. Together these data indicated that the rabbit IVD was dramatically more stable than the rat IVD, which showed culture-related degenerative changes. Based on these findings we conclude that the rabbit motion segments are a superior model for mechanobiologic studies.


Extensive remodeling of the presynaptic cytomatrix upon homeostatic adaptation to network activity silencing.
Global changes of activity in neuronal networks induce homeostatic adaptations of synaptic strengths, which involve functional remodeling of both presynaptic and postsynaptic apparatuses. Despite considerable advances in understanding cellular properties of homeostatic synaptic plasticity, the underlying molecular mechanisms are not fully understood. Here, we explored the hypothesis that adaptive homeostatic adjustment of presynaptic efficacy involves molecular remodeling of the release apparatus including the presynaptic cytomatrix, which spatially and functionally coordinates neurotransmitter release. We found significant downregulation of cellular expression levels of presynaptic scaffolding proteins Bassoon, Piccolo, ELKS/CAST, Munc13, RIM, liprin-α, and synapsin upon prolonged (48 h) activity depletion in rat neuronal cultures. This was accompanied by a general reduction of Bassoon, Piccolo, ELKS/CAST, Munc13, and synapsin levels at synaptic sites. Interestingly, RIM was upregulated in a subpopulation of synapses. At the level of individual synapses, RIM quantities correlated well with synaptic activity, and a constant relationship between RIM levels and synaptic activity was preserved upon silencing. Silencing also induced synaptic enrichment of other previously identified regulators of presynaptic release probability, i.e., synaptotagmin1, SV2B, and P/Q-type calcium channels. Seeking responsible cellular mechanisms, we revealed a complex role of the ubiquitin-proteasome system in the functional presynaptic remodeling and enhanced degradation rates of Bassoon and liprin-α upon silencing. Together, our data indicate a significant molecular reorganization of the presynaptic release apparatus during homeostatic adaptation to network inactivity and identify RIM, synaptotagmin1, Ca(v)2.1, and SV2B as molecular candidates underlying the main silencing-induced functional hallmark at presynapse, i.e., increase of neurotransmitter release probability.


Hepatitis E: An emerging infection in high income countries.
Hepatitis E virus (HEV) genotype 3 is the most recently characterized hepatotropic virus and is increasingly being recognized as the cause of unexplained liver disease in many western countries. Although asymptomatic in most cases, HEV GT3 may be responsible for a wide range of illnesses, from mild to fulminant acute hepatitis, and also chronic hepatitis in immunocompromised patients. Extrahepatic manifestations have been occasionally described. Anti-HEV antibody detection by immunoassays is hampered by moderate test accuracy particularly in immunocompromised hosts while a WHO international standard for molecular detection of HEV RNA by RT-PCR has recently been introduced. This review describes the basic virology, epidemiology, clinical virology and treatment of HEV GT3 infections in high income countries.


Effect of vitamin D on endothelial progenitor cells function.
Endothelial progenitor cells (EPCs) are a population of bone marrow-derived cells, which have an important role in the process of endothelialization and vascular repair following injury. Impairment of EPCs, which occurs in patients with diabetes, was shown to be related to endothelial dysfunction, coronary artery disease (CAD) and adverse clinical outcomes. Recent evidence has shown that calcitriol, the active hormone of vitamin D, has a favorable impact on the endothelium and cardiovascular system. There is limited data on the effect of vitamin D on EPCs function. To examine the in vitro effects of Calcitriol on EPCs from healthy subjects and patients with diabetes. Fifty-one patients with type 2 diabetes (60±11 years, 40% women, HbA1C: 9.1±0.8%) and 23 healthy volunteers were recruited. EPCs were isolated and cultured with and without calcitriol. The capacity of the cells to form colony-forming units (CFUs), their viability (measured by MTT assay), KLF-10 levels and angiogenic markers were evaluated after 1 week of culture. In diabetic patients, EPC CFUs and cell viability were higher in EPCs exposed to calcitriol vs. EPCs not exposed to calcitriol [EPC CFUs: 1.25 (IQR 1.0-2.0) vs. 0.5 (IQR 0.5-1.9), p < 0.001; MTT:0.62 (IQR 0.44-0.93) vs. 0.52 (IQR 0.31-0.62), p = 0.001]. KLF-10 levels tended to be higher in EPCs exposed to vitamin D, with no differences in angiopoietic markers. In healthy subjects, calcitriol supplementation also resulted in higher cell viability [MTT: 0.23 (IQR 0.11-0.46) vs. 0.19 (0.09-0.39), p = 0.04], but without differences in CFU count or angiopoietic markers. In patients with diabetes mellitus, in vitro vitamin D supplementation improved EPCs capacity to form colonies and viability. Further studies regarding the mechanisms by which vitamin D exerts its effect are required.


[Epidemiology and clinical profile of knee osteoarthrosis in the elderly].
Osteoarthris represents one of the most frequent degenerative pathologies. Its prevalence increases with the age as well as the functional consequences which are more considerable at the elderly population. aim : study the epidemiology and clinical features of knee osteoarthritis of older patient. methods: retrospective study made in the department of physical and rehabilitation medicine of the military Tunis hospital, on a sample of 60 patients having osteoarthritis, divided in two groups, the one is constituted by 30 subjects of 65 and more years old, other one of 30 adults aged between 30 and 55 years old. All the patients had a clinical and functional evaluation. results: the comparison between both groups showed a statistically significant difference (P < 0.05) in the following items: the severity of the pain, the bilateral hydarthrosis, the muscular strength of quadriceps, hamstrings and their retraction, the severe reduction of walking perimeter, and the bicompartimental lesion of both knees. clinical and sociofunctional features of knee osteoarthritis in the elderly patient require adapted and multidisciplinary management, in order to avoid the potential impact of knee osteoarthritis on the function and quality of life of the patient.


Lumbar Extradural Pseudogout Mass Manifesting as Radiculopathy: A Case Report.
Calcium pyrophosphate dihydrate (CPPD) disease, also known as pyrophosphate arthropathy or pseudogout, is defined as CPPD deposition within the articular cartilage. It was first described in 1962. The representative locations where CPPD disease occurs include the most common knee joint, followed by the wrist joint. Joint swelling and pain are the most common clinical presentations, and the typical differential diagnosis is degenerative arthritis. Microscopically, the specimen demonstrates numerous positively birefringent rhomboid shaped crystals when examined under polarized light. We present a 70-year-old female with right painful sciatica accompanied by coexisting affected limb soreness and clumsiness. Her final diagnosis was unusual lumbar extradural tumoral pseudogout that was worth noticing. Tumoral CPPD deposition was excised after laminectomy. Subsequently, her symptoms were abated postoperatively without a need for more analgesics. Her neurological function was properly recovered. This is a rare report to proffer pseudogout in an unfamiliar lumbar extradural location, which is an unexpected diagnosis. Making a precise tentative diagnosis for the ongoing disease entity might be difficult for the clinicians because the clinical manifestations of this pathology are similar to those of other common degenerative lumbar spinal diseases.


BMI is a poor predictor of adiposity in young overweight and obese children.
The body mass index (BMI) is a simple and widely utilized screening tool for obesity in children and adults. The purpose of this investigation was to evaluate if BMI could predict total fat mass (TFM) and percent body fat (%FAT) in a sample of overweight and obese children. In this observational study, body composition was measured by dual energy x-ray absorptiometry (DXA) in 663 male and female overweight and obese children at baseline within a multidisciplinary, pediatric fitness clinic at an academic medical center. Univariate and multivariate regression analyses were conducted to evaluate whether BMI z-score (BMIz) predicts TFM or %FAT. The BMIz, sex and age of subjects were identified as significant predictors for both TFM and %FAT. In subjects younger than 9 years, the BMIz was a weak to moderate predictor for both TFM (R2 = 0.03 for males and 0.26 for females) and %FAT (R2 = 0.22 for males and 0.38 for females). For subjects between 9 and 18 years, the BMIz was a strong predictor for TFM (R2 between 0.57 and 0.73) while BMIz remained only moderately predictive for %FAT (R2 between 0.22 and 0.42). These findings advance the understanding of the utility and limitations of BMI in children and adolescents. In youth (9-18y), BMIz is a strong predictor for TFM, but a weaker predictor of relative body fat (%FAT). In children younger than 9y, BMIz is only a weak to moderate predictor for both TFM and %FAT. This study cautions the use of BMIz as a predictor of %FAT in children younger than 9 years.


Delirium after emergency hip surgery - common and serious, but rarely consented for.
A quarter of patients admitted with a proximal femoral fracture suffer from an acute episode of delirium during their hospital stay. Yet it is often unrecognised, poorly managed, and rarely discussed by doctors. Delirium is important not only to the affected individuals and their families, but also socioeconomically to the broader community. Delirium increases mortality and morbidity, leads to lasting cognitive and functional decline, and increases both length of stay and dependence on discharge. Delirium should be routinely and openly discussed by all members of the clinical team, including surgeons when gaining consent. Failing to do so may expose surgeons to claims of negligence. Here we present a concise review of the literature and discuss the epidemiology, causative factors, potential consequences and preventative strategies in the perioperative period.


Prenatal Growth Patterns and Birthweight Are Associated With Differential DNA Methylation and Gene Expression of Cardiometabolic Risk Genes in Human Placentas: A Discovery-Based Approach.
Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth-altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome-wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1, IL10), thereby establishing transcriptional effects toward assigning functional significance. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment, as it affects fetal growth patterns. We speculate that these observed changes may affect risk for offspring in developing adult cardiometabolic disease.


The importance of polarizability: comparison of models of carbon disulphide in the ionic liquids [C1C1im][NTf2] and [C4C1im][NTf2].
The local environment of CS2 and in solution in two ionic liquids ([C1C1im][NTf2] and [C4C1im][NTf2]) are investigated by atomistic simulation and compared with that in neat CS2. The intermolecular vibrational densities of states of CS2 are calculated and compared with experimental OHD-RIKES spectra. The fair agreement of the results from solutions but poor agreement of the results from neat CS2 suggest that while collective effects are unimportant in solutions, they have a major effect on the OHD-RIKES spectrum of neat CS2. Comparing polarizable and unpolarizable models for CS2 emphasizes the importance of polarizability in determining local structure.


Phase-space deconvolution for light field microscopy.
Light field microscopy, featuring with snapshot large-scale three-dimensional (3D) fluorescence imaging, has aroused great interests in various biological applications, especially for high-speed 3D calcium imaging. Traditional 3D deconvolution algorithms based on the beam propagation model facilitate high-resolution 3D reconstructions. However, such a high-precision model is not robust enough for the experimental data with different system errors such as optical aberrations and background fluorescence, which bring great periodic artifacts and reduce the image contrast. In order to solve this problem, here we propose a phase-space deconvolution method for light field microscopy, which fully exploits the smoothness prior in the phase-space domain. By modeling the imaging process in the phase-space domain, we convert the spatially-nonuniform point spread function (PSF) into a spatially-uniform one with a much smaller size. Experiments on various biological samples and resolution charts are demonstrated to verify the contrast enhancement with much fewer artifacts and 10-times less computational cost by our method without any hardware modifications required.


Cortical output to fast and slow muscles of the ankle in the rhesus macaque.
The cortical control of fast and slow muscles of the ankle has been the subject of numerous reports yielding conflicting results. Although it is generally agreed that cortical stimulation yields short latency facilitation of fast muscles, the effects on the slow muscle, soleus, remain controversial. Some studies have shown predominant facilitation of soleus from the cortex while others have provided evidence of differential control in which soleus is predominantly inhibited from the cortex. The objective of this study was to investigate the cortical control of fast and slow muscles of the ankle using stimulus triggered averaging (StTA) of EMG activity, which is a sensitive method of detecting output effects on muscle activity. This method also has relatively high spatial resolution and can be applied in awake, behaving subjects. Two rhesus macaques were trained to perform a hindlimb push-pull task. Stimulus triggered averages (StTAs) of EMG activity (15, 30, and 60 μA at 15 Hz) were computed for four muscles of the ankle [tibialis anterior (TA), medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus] as the monkeys performed the task. Poststimulus facilitation (PStF) was observed in both the fast muscles (TA, MG, and LG) as well as the slow muscle (soleus) and was as common and as strong in soleus as in the fast muscles. However, while poststimulus suppression (PStS) was observed in all muscles, it was more common in the slow muscle compared to the fast muscles and was as common as facilitation at low stimulus intensities. Overall, our results demonstrate that cortical facilitation of soleus has an organization that is very similar to that of the fast ankle muscles. However, cortical inhibition is organized differently allowing for more prominent suppression of soleus motoneurons.


The structure of a ferrous heme-nitro species in the binuclear heme a3/CuB center of ba3-cytochrome c oxidase as determined by resonance Raman spectroscopy.
Members of the cytochrome c oxidase family exhibit nitrite reductase activity. In this work, we have characterized a ferrous heme a3-nitro species in ba3-oxidase by resonance Raman spectroscopy. This provides the first evidence for the structure of a nitrite-bound species in the binuclear heme/copper center of cytochrome c oxidases.


Adolescents' perspectives and food choice behaviors in terms of the environmental impacts of food production practices: application of a psychosocial model.
The objective of this study was to investigate adolescents' perspectives about the environmental impacts of food production practices and whether these perspectives are related to their food choice. Food choice was operationalized as consumption and purchase of organic foods and locally grown foods. A survey questionnaire was administered to a convenience sample of adolescents and analyzed for descriptive information and relationships among variables. Subjects were 651 ethnically diverse, urban and suburban high school senior students in a major metropolitan area. Variables of an Expanded Theory of Planned Behavior were measured including beliefs, attitudes, perceived social influences, motivation to comply, perceived behavioral control, self-identity, perceived responsibility, behavioral intention, and behavior. Descriptive statistics, Pearson correlation coefficients, and stepwise multiple regression analyses were used. Surveyed adolescents did not have strong or consistent beliefs or attitudes about the environmental impact of food production practices. Cognitive-motivational processes were at work, however, since their perspectives were significantly correlated with behavioral intentions and food choice behaviors. Behavioral intention was best accounted for by attitudes and perceived social influences (and perceived responsibility for organic food), and behavior was best accounted for by behavioral intentions, beliefs, and perceived social influences (and self-identity for local food). There is a need to make salient to adolescents the environmental impact of food production practices through both cognitive and experiential approaches.


A computerized fetal monitoring system.
A computerized fetal monitoring system has been developed at the Cedars-Sinai Medical Center in Los Angeles, California. It utilizes unmodified fetal monitors feeding fetal heart rate and uterine pressure data into a minicomputer. The overall accuracy on internal monitoring is 91%. The concept of on-line computer analysis of fetal monitoring records has met with clinical acceptance and is utilized for all patients in labor at the Cedars-Sinai Medical Center.


Laparoscopic Management of Dilatation of Excluded Stomach After Roux-en-Y Gastric Bypass.
Roux-en-Y gastric bypass (RYGB) is considered as the gold standard for surgical management of morbid obesity due to its good results on weight loss and correction of comorbidities related to obesity and its few complication rates. Here, we describe a present strategy for dealing with an unusual complication after RYGB, responsible for chronic pain, as a chronic dilatation of excluded stomach. The video shows our laparoscopic treatment of an excluded gastric fundus dilatation. A 21-year-old woman with history of RYGB was admitted in our center for recurrent abdominal pain. Many consultations have been performed before for the same reason and without explanation for this chronic abdominal pain. We found that a dilatation of the excluded gastric fundus was responsible for recurrent abdominal pain and thus required revisional surgery. An abdominal computed tomography with oral contrast study showed an atypical dilatation of the excluded stomach without gastro-gastric fistula or others abnormal findings. Intra-operative exploration then revealed multiple adhesions. During surgery, released of the excluded stomach allow to confirm a dilatation of the excluded fundus due to error in stapling when performing the vertical part of the gastric pouch of the RYGB. We resected the excluded dilated gastric fundus. An uneventful post-operative course enabled rapid discharge (post-operative day 3). Dilatation of the excluded gastric pouch due to staple line misfiring during RYGB is a rare complication and can explain chronic abdominal pain. Laparoscopy can be useful to confirm the diagnosis and allow treatment using gastric resection in our case.


Personalized Regenerative Medicine.
Personalized medicine as a novel field of medicine refers to the prescription of specific therapeutics procedure for an individual. This approach has established based on pharmacogenetic and pharmacogenomic information and data. The terms precision and personalized medicines are sometimes applied interchangeably. However, there has been a shift from "personalized medicine" towards "precision medicine". Although personalized medicine emerged from pharmacogenetics, nowadays it covers many fields of healthcare. Accordingly, regenerative medicine and cellular therapy as the new fields of medicine use cell-based products in order to develop personalized treatments. Different sources of stem cells including mesenchymal stem cells, embryonic stem cells and induced pluripotent stem cells (iPSCs) have been considered in targeted therapies which could give many advantages. iPSCs as the novel and individual pluripotent stem cells have been introduced as the appropriate candidates for personalized cell therapies. Cellular therapies can provide a personalized approach. Because of person-to-person and population differences in the result of stem cell therapy, individualized cellular therapy must be adjusted according to the patient specific profile, in order to achieve best therapeutic results and outcomes. Several factors should be considered to achieve personalized stem cells therapy such as, recipient factors, donor factors, and the overall body environment in which the stem cells could be active and functional. In addition to these factors, the source of stem cells must be carefully chosen based on functional and physical criteria that lead to optimal outcomes.


Systematic identification of mitochondrial proteins by LC-MS/MS.
In eukaryotic cells, the mitochondrion is the key organelle for cellular respiration. Mitochondrial proteome analysis is difficult to perform by the classical proteomic approach involving two-dimensional gel electrophoresis (2DE), because this organelle contains a large number of membrane-associated and highly alkaline proteins usually requiring specific treatments to be successfully analyzed. Here, an alternative approach was evaluated and led to the rapid and sensitive identification of approximately 35% of the yeast mitochondrial proteins. It consists of an SDS-PAGE gel electrophoresis of the total mitochondrial protein in combination with the LC-MS/MS analysis of the digestion products of gel slices. The use of only 40 microg of mitochondrial protein enabled the identification of 179 different gene products divided into similar proportions of membrane and soluble proteins. The distribution of the identified proteins in terms of pI and hydrophobicity revealed that the present analytical strategy is largely unbiased. The identification of 28 proteins of previously unknown subcellular localization demonstrated the ability of SDS-PAGE-LC-MS/MS to rapidly supplement the knowledge of the mitochondrial proteome.


Increased ERG a- and b-wave amplitudes in 7- to 10-year-old children resulting from prenatal lead exposure.
To determine the dose-response relationship between blood lead concentration ([PbB]) and scotopic ERG amplitude in 7- to 10-year-old children with lifetime lead exposure. Full-field flash scotopic ERGs were recorded over a 4-log-unit range in 45 dark-adapted children with normal visual acuity. [PbB] was measured throughout pregnancy and postnatal development, and the subjects' [PbB] levels were grouped at each age by tertiles. The median [PbB] during pregnancy was, from lowest to highest tertile, 2.5 to 5.0, 7.5 to 9.0, and 14.0 to 16.5 microg/dL, and after birth was 4.0 to 8.0, 6.0 to 14.5, and 7.5 to 21.0 microg/dL. Only maternal [PbB] at 12 weeks of pregnancy showed a significant dose-response relationship with the ERG measures, so that with increasing [PbB] there were significant increases in leading-edge a-wave amplitude, peak a-wave amplitude, and b-wave amplitude and sensitivity, with no changes in implicit times. Data analyses showed that children whose mothers had [PbB] of 10.5 microg/dL or more at 12 weeks of pregnancy had relatively increased a- and b-waves. Lead exposure during the first trimester of pregnancy produces dose-dependent increases in scotopic a- and b-wave amplitudes in 7- to 10-year-old children. The results suggest that the increases in a- and b-wave amplitudes originate from rods; however, the increased b-wave amplitude and sensitivity may also originate in the inner retina. These alterations occurred at maternal [PbB] at or below currently accepted safe levels. These novel findings reveal that the developing retina is a sensitive target for lead and suggest that lead-exposed children be examined for possible future visual system deficits.


New species of Indocloeon Müller-Liebenau from South-East Asia (Ephemeroptera, Baetidae).
One new species of Indocloeon Müller-Liebenau from Brunei, I. spathasetissp. n., and one new species from Indonesia, I. timorensesp. n., are described and illustrated based on their larvae. The total number of known Indocloeon species increases from two to four and the generic attributes of the larvae are amended based on the examination of the new species. Results on the genetics of some species (COI) as well as comments on the distribution of I. indonesiae Kluge are also provided.


Treatment of intrauterine and large pedunculated subserosal leiomyomata with sequential uterine artery embolization and myomectomy.
Successful clinical outcomes were obtained after a combined therapy of uterine artery embolization (UAE) and subsequent myomectomy for gigantic subserosal leiomyoma exceeding 1,000 cm3 in volume on a short stalk and multiple intrauterine leiomyomata in young patients who desired fertility and uterine preservation. UAE effectively treated symptomatic multiple intramural and submucosal leiomyomata for menorrhagia symptoms, which also facilitated uncomplicated subsequent myomectomy with devascularized gigantic leiomyoma for the treatment of bulk symptoms.


[Disorders of the immune system in benign lesions and cancer of the breast].
Immunologic vigor was studied in 225 cases of breast cancer at various stages, 99 patients with benign lesions of the breast and 154 healthy donors. The parameters of cell-mediated immunity under study included total, active and neuraminidase T-lymphocyte levels, concentration of T-lymphocyte subsets (Tm, T gamma, theophylline--sensitive and theophylline--resistant) and their profile, functional activity of lymphocytes in blastogenic reaction with PHA and natural killer levels. Also, such humoral immunity indexes as B-lymphocytes and immunoglobulins A, M and C were evaluated. Significant changes in functional activity of the immune system (mainly, its T-cell--mediated component) were identified as early as at the initial stages of breast cancer development and they became more pronounced as tumor advanced. Also, at initial stages, both T-lymphocyte and natural killer functional activity started to flag.


Practice to research: integrating evidence-based practices with culture and context.
There are ways to integrate culturally competent services (CCS) and evidence-based practices (EBP) which can improve the experiences of patients and their families and communities when faced with health problems, as well as the effectiveness and positive experiences of practitioners. CCS and EBP evidence should be jointly deployed for helping patients and clinicians. Partnership research models are useful for achieving the integration of CCS and EBP, since they involve close observation of and participation by clinicians and practitioners in the research process, and often use integrated qualitative and quantitative mixed methods. We illustrate this with 3 examples of work that can help integrate CCS and EBP: ongoing collection of information from patients, clinicians and staff, or "evidence farming"; close study and continuous improvement of activities and accommodations; and use of evidence of tacit, implicit cultural scripts and norms, such as being "productive," as well as explicit scripts. From a research practice point of view, collaborative partnerships will likely produce research with culture and context bracketed in, and will contribute stronger research models, methods, and units of analysis.


Measurement of contrast sensitivity and glare under mesopic and photopic conditions following wavefront-guided and conventional LASIK surgery.
To compare contrast and glare vision in a prospective study of eyes treated using conventional and wavefront-guided LASIK surgery. The reproducibility of a glaremeter device used to quantitatively measure glare and halo was also determined. Ninety-two eyes of 46 patients underwent conventional LASIK surgery and 104 eyes of 52 patients underwent wavefront-guided LASIK surgery. Visual acuity, glare disability measured using a glaremeter, and contrast sensitivity assessed using a Pelli-Robson chart were measured monthly for 6 months postoperatively. Glaremeter testing was performed under both mesopic (5.4 +/- 0.4 cd/m2) and photopic (78.3 +/- 4.4 cd/m2) conditions. To evaluate the reproducibility of the glaremeter, 36 eyes of 18 nonoperated myopic patients were tested. The coefficient of variation and the reliability coefficient for the glare test were 13.6% and 95.2%, respectively. The glaremeter showed that glare disability under mesopic conditions differed between conventional and wavefront-guided LASIK eyes over 6-month follow-up (907.5 +/- 491.5 vs 986.1 +/- 448.0 pixels preoperatively and 1717.1 +/- 521.2 vs 1407.8 +/- 411.3 pixels at 6 months, P<.0001). At 6 months, contrast sensitivity log values were 1.62 +/- 0.31 and 1.78 +/- 0.34 for conventional and wavefront-guided LASIK eyes, respectively (P=.010). The visual complaint score was lower in the wavefront-guided LASIK group (P=.0116). Compared to conventional ablation, wavefront-guided ablation provided superior outcomes in terms of postoperative glare under mesopic conditions, subjective complaints, and contrast sensitivity. In addition, it appears the glaremeter can be used for clinical quantitative evaluation of glare and halo.


What can dissaving tell us about catastrophic costs? Linear and logistic regression analysis of the relationship between patient costs and financial coping strategies adopted by tuberculosis patients in Bangladesh, Tanzania and Bangalore, India.
Tuberculosis (TB) is a major global public health problem which affects poorest individuals the worst. A high proportion of patients incur 'catastrophic costs' which have been shown to result in severe financial hardship and adverse health outcomes. Data on catastrophic cost incidence is not routinely collected, and current definitions of this indicator involve several practical and conceptual barriers to doing so. We analysed data from TB programmes in India (Bangalore), Bangladesh and Tanzania to determine whether dissaving (the sale of assets or uptake of loans) is a useful indicator of financial hardship. Data were obtained from prior studies of TB patient costs in Bangladesh (N = 96), Tanzania (N = 94) and Bangalore (N = 891). These data were analysed using logistic and linear multivariate regression to determine the association between costs (absolute and relative to income) and both the presence of dissaving and the amounts dissaved. After adjusting for covariates such as age, sex and rural/urban location, we found a significant positive association between the occurrence of dissaving and total costs incurred in Tanzania and Bangalore. We further found that, for patients in Bangalore an increase in dissaving of $10 USD was associated with an increase in the cost-income ratio of 0.10 (p < 0.001). For low-income patients in Bangladesh, an increase in dissaving of $10 USD was associated with an increase in total costs of $7 USD (p <0.001). Dissaving is potentially a convenient proxy for catastrophic costs that does not require usage of complex patient cost questionnaires. It also offers an informative indicator of financial hardship in its own right, and could therefore play an important role as an indicator to monitor and evaluate the impact of financial protection and service delivery interventions in reducing hardship and facilitating universal health coverage. Further research is required to understand the patterns and types of dissaving that have the strongest relationship with financial hardship and clinical outcomes in order to move toward evidence-based policy making.


Chemical Approaches to Inhibiting the Hepatitis B Virus Ribonuclease H.
Hepatitis B virus (HBV) chronically infects >250 million people and kills nearly a million annually, and current antivirals cannot clear the infection or adequately suppress disease. The virus replicates by reverse transcription, and the dominant antiviral drugs are nucleos(t)ide analogs that target the viral reverse transcriptase. We are developing antivirals targeting the other essential viral enzymatic activity, the ribonuclease H (RNaseH). HBV RNaseH inhibitors with efficacies in the low micromolar to nanomolar range against viral replication in culture have been identified in the α-hydroxytropolone and hydroxyimide chemotypes. Here, we review the promise of RNaseH inhibitors, their current structure-activity relationships, and challenges to optimizing the inhibitors into leads for clinical assessment.


Treatment of infections in non-neutropenic patients with cancer, AIDS, or renal transplant using ciprofloxacin.
Infective complications not only remain the major factor in preventing a large proportion of cancer patients from achieving a complete remission, but also greatly influence the outcome of immunosuppressed transplant recipients and are a prominent problem in subjects affected by AIDS. We report the results of 73 patients, 54 males and 19 females with a mean age of 61.4 +/- 15.1 years affected by solid cancer (64 pts), AIDS (6 pts) or with kidney transplant (3 pts), treated with ciprofloxacin 250 mg bid (21 pts) or 500 mg bid (52 pts) for respiratory tract infections (41 cases), urinary tract infections (22), septicemia (5) or other infections (5). The mean course of therapy was 9.6 +/- 5.7 days and led to a complete resolution of symptoms in 66 (90.4%) patients, improvement in 6 (8.2%), while the clinical picture was unaffected in 1 (1.4%). Candida superinfection occurred in one case and only four patients experienced side effects. Ciprofloxacin results to be an effective antibacterial agent in a high risk population.


Association of Provider Specialty and Multidisciplinary Care With Hepatocellular Carcinoma Treatment and Mortality.
Little is known about provider and health system factors that affect receipt of active therapy and outcomes of patients with hepatocellular carcinoma (HCC). We investigated patient, provider, and health system factors associated with receipt of active HCC therapy and overall survival. We performed a national, retrospective cohort study of all patients diagnosed with HCC from January 1, 2008 through December 31, 2010 (n = 3988) and followed through December 31 2014 who received care through the Veterans Administration (128 centers). Outcomes were receipt of active HCC therapy (liver transplantation, resection, local ablation, transarterial therapy, or sorafenib) and overall survival. In adjusted analyses, receiving care at an academically affiliated Veterans Administration hospital (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.60-2.41) or a multi-specialist evaluation (OR, 1.60; 95% CI, 1.15-2.21), but not review by a multidisciplinary tumor board (OR, 1.19; 95% CI, 0.98-1.46), was associated with a higher likelihood of receiving active HCC therapy. In time-varying Cox proportional hazards models, liver transplantation (hazard ratio [HR], 0.22; 95% CI, 0.16-0.31), liver resection (HR, 0.38; 95% CI, 0.28-0.52), ablative therapy (HR, 0.63; 95% CI, 0.52-0.76), and transarterial therapy (HR, 0.83; 95% CI, 0.74-0.92) were associated with reduced mortality. Subspecialist care by hepatologists (HR, 0.70; 95% CI, 0.63-0.78), medical oncologists (HR, 0.82; 95% CI, 0.74-0.91), or surgeons (HR, 0.79; 95% CI, 0.71-0.89) within 30 days of HCC diagnosis, and review by a multidisciplinary tumor board (HR, 0.83; 95% CI, 0.77-0.90), were associated with reduced mortality. In a retrospective cohort study of almost 4000 patients with HCC cared for at VA centers, geographic, provider, and system differences in receipt of active HCC therapy are associated with patient survival. Multidisciplinary methods of care delivery for HCC should be prospectively evaluated and standardized to improve access to HCC therapy and optimize outcomes.


Insulin regulates brain function, but how does it get there?
We have learned over the last several decades that the brain is an important target for insulin action. Insulin in the central nervous system (CNS) affects feeding behavior and body energy stores, the metabolism of glucose and fats in the liver and adipose, and various aspects of memory and cognition. Insulin may even influence the development or progression of Alzheimer disease. Yet, a number of seemingly simple questions (e.g., What is the pathway for delivery of insulin to the brain? Is insulin's delivery to the brain mediated by the insulin receptor and is it a regulated process? Is brain insulin delivery affected by insulin resistance?) are unanswered. Here we briefly review accumulated findings affirming the importance of insulin as a CNS regulatory peptide, examine the current understanding of how peripheral insulin is delivered to the brain, and identify key gaps in the current understanding of this process.


Occupational exposure assessment of highway toll station workers to vehicle engine exhaust.
Toll station workers are occupationally exposed to vehicle engine exhaust, a complex mixture of different chemical substances, including carcinogenic compounds. Therefore, a study was carried out on attendants of two highway toll stations to describe their occupational exposure to vehicle engine exhaust, based on a worst-case scenario approach. Personal sampling was conducted during the day shift for all attendants, testing for three groups of chemical substances: polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) and aldehydes (formaldehyde and acrolein). Concentrations of total PAH, BTEX (benzene, toluene, ethylbenzene, and xylenes) and formaldehyde content varied between 97.60-336.08 ng/m3, 5.01-40.52 μg/m3, and 0.06-19.13 μg/m3, respectively. No clear relationships could be established between exposure levels and the number of vehicles. Furthermore, no differences were found between truck versus car lanes, or inside versus outside the tollbooth. Not all the detected VOCs were related to vehicle exhaust; some were consistent with the use of cleaning products. The measured concentrations were far below the established occupational exposure limits, but tended to be higher than values reported for outdoor urban environments. There are very few international studies assessing occupational exposures among toll station workers, and this is the first such study to be conducted in Spain. The results suggest that further, more detailed studies are necessary to characterize exposure properly, and ones which include other airborne pollutants, such as ultrafine particles. The comparison of the results to other similar studies was difficult, since no data related to some important exposure determinants have been provided. Therefore, it is recommended that these determinants be considered in future studies.


Association Between Lateralized Periodic Discharge Amplitude and Seizure on Continuous EEG Monitoring in Patients With Structural Brain Abnormality in Critical Illness.
To investigate the association between lateralized periodic discharge (LPD) amplitude and seizure risk on an individual level in patients with structural brain abnormality. Retrospective case-control study of patients with structural brain abnormality undergoing continuous EEG monitoring was performed. We included 10 patients with LPDs and seizures as cases and 10 controls, patients with LPDs without seizure. Analysis was performed with a mixed-effects model with primary outcome measure of number of seizures per 8-h EEG epoch with fixed effects being variables of interest and random effect being subject ID. Epochs with seizures showed a higher absolute amplitude (corrected p = 0.04) and a higher relative amplitude (corrected p = 0.04) of LPDs. Additionally, the number of seizures was higher in epochs that had LPDs with plus features (uncorrected p = 0.002) and LPDs with higher relative amplitude (uncorrected p = 0.005). Higher LPD amplitude is associated with increased risk of seizures on an individual patient level. A decreasing amplitude is suggestive of decreasing seizure risk, and may in fact be suggestive of decreasing ictal character of LPDs.


The effect of heating against Cryptosporidium oocysts.
The effect of heat treatment was examined against oocysts of Cryptosporidium parvum, Cryptosporidium muris and chicken Cryptosporidium sp. isolated in Japan. The oocysts of these species were exposed at 50, 55, 60 and 70 degrees C for 5, 15, 30 and 60 sec in water bath, respectively. To determine the infectivity of heated oocysts, the nice and chickens were inoculated with the treated oocysts and the oocyst output in the feces after inoculation was examined. In C. parvum and chicken Cryptosporidium sp., the oocysts were not detected from mice or chickens which were received oocysts heated at 55 degrees C for 30 sec, 60 degrees C for 15 sec and 70 degrees C for 5 sec. In C. muris, the oocysts were not detected from mice which were received oocysts heated at 55 degrees C for 15 sec, 60 degrees C for 15 sec and 70 degrees C for 5 sec. Consequently, it was clarified that the infectivity of Cryptosporidium oocysts to mice and chickens was lost by heating at 55 degrees C for 30 sec, 60 degrees C for 15 sec and 70 degrees C for 5 sec.


Purple acid phosphatases of Arabidopsis thaliana. Comparative analysis and differential regulation by phosphate deprivation.
Purple acid phosphatases (PAPs) are members of the metallo-phosphoesterase family. They are characterized by the presence of seven conserved amino acid residues involved in coordinating the dimetal nuclear center in their reactive site. We compared the 29 PAPs predicted for Arabidopsis thaliana in their varieties of potential metal-ligating residues. Although 24 members possessed sets of metal-ligating residues typical of known PAPs, 1 member lacked four of the seven residues. For the remaining four members, potential metal-ligating residues were generally more similar to those in metal-dependent exonucleases and related proteins. Evidence was obtained for the expression of the majority of the 29 PAPs. To facilitate future investigations, a scheme for naming Arabidopsis PAPs and a system for classifying the 29 PAPs are proposed. The cDNA sequences and the responses to phosphate deprivation of seven Arabidopsis PAPs (AtPAP7-AtPAP13) were characterized. For some AtPAPs analyzed, there were fully processed transcripts as well as splice variants. The splice variants of AtPAP10 were found to associate with polyribosomes and may be translated into a NH(2)-terminal truncated protein. Phylogenetic investigations showed that AtPAPs 7 and 8, together with similar enzymes from other plant species, formed the low molecular weight plant PAP group. Members of this group were more closely related to PAPs from mammalian cells. AtPAPs 9-13, together with kidney bean PAP, formed the high molecular weight PAP group. In phosphate deprivation experiments, gene transcription of AtPAP11 and AtPAP12 was induced and increased, respectively, whereas that of the remaining five AtPAPs was not affected by phosphate deprivation. The present work demonstrates that structure variation and expression regulation of plant PAPs are more complex than previously described and provides a framework for comprehensive molecular genetic and biochemical studies of all Arabidopsis PAPs in the future.


Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates.
The neonates, particularly small-for-gestational-age (SGA) ones, are susceptible to various microbial infections. Natural killer (NK) cells are critical components of host innate immunity system and the main source of the inflammatory cytokines, which provide critical protection during the early phase of viral infections before the development of an appropriate adaptive immune response. However, little is known about the antiviral effects of NK cells in neonates especially the SGA population. Herein, a prospective descriptive study was performed to determine the differences of NK cell immunity among adults, appropriate-for gestational-age (AGA) and SGA neonates. Adults have much higher NK cell number in peripheral blood than that in cord blood from neonates. In response to influenza virus stimulation, neonatal NK cells, especially SGA baby cells, expressed significantly lower antiviral cytokines including perforin, interferon (IFN)-γ and tumor-necrosis factor (TNF)-α responses than adult NK cells. In addition, the antiviral cytokine responses of NK cells were positively correlated with neonatal birth weight. Our data suggested that the depressed antiviral activity and less frequency of NK cells are likely to be responsible for the high susceptibility to microbial infection in neonates, at least in part. Improving the function of innate immunity may provide a new way to defend virus infection.


Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography.
The effects of therapeutic hypothermia (TH) on hemodynamics in newborns with hypoxic-ischemic encephalopathy (HIE) were evaluated. Thirty-two neonates (gestational age, 39.4 ± 1.3 weeks) who had TH for HIE and echocardiographic hemodynamic assessments during TH and post-TH period were studied. Gestational-age-matched 34 healthy neonates were enrolled for comparison. During TH, patients had significantly decreased left ventricular cardiac output (LVCO), descending aorta blood flow (DABF), and DABF/LVCO ratio, and increased resistive index of DA compared to controls. Upper body blood flow (UBBF) remained unchanged but UBBF/LVCO ratio significantly increased during TH. Urine output decreased significantly during TH and increased after rewarming, and showed significant positive correlation with DABF/LVCO ratio. Sixteen patients (50%) showed hypoxic-ischemic (HI) lesions on brain magnetic resonance imaging (MRI) and had significantly increased UBBF/LVCO ratio during TH compared to patients without HI lesions. Patients with UBBF/LVCO ratio >55% had significantly higher risk of having HI lesions on brain MRI (odds ratio 13.0; 95% CI, 2.4-70.2). Decrease in cardiac output and descending aorta blood flow, and preferential cerebral redistribution of cardiac output along with an increase in systemic peripheral vascular resistance may affect systemic organ perfusion and cerebral metabolism.


[Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock Due to Fulminant Myocarditis].
This article presents a clinical case of a 40-year-old woman with fulminant myocarditis which progressed rapidly to the development of cardiogenic shock resistant to standard intensive care, but with a positive response to extracorporeal membrane oxygenation.


Antitubercular cassane furanoditerpenoids from the roots of Caesalpinia pulcherrima.
Activity-guided fractionation of a root extract of Caesalpinia pulcherrima led to the isolation of two cassane-furanoditerpenoids, 6 beta-benzoyl-7 beta-hydroxyvouacapen-5 alpha-ol (1) and 6 beta-cinnamoyl-7beta-hydroxyvouacapen-5 alpha-ol (2). Compound 2 showed strong antitubercular activity with a minimum inhibitory concentration (MIC) of 6.25 microg/mL, whereas the benzoyl analogue (1) was less active (MIC 25 microg/mL). Both compounds expressed moderate cytotoxic activity towards KB (human oral carcinonoid cancer), BC (human breast cancer) and NCl-H187 (small cell lung cancer) cell lines.


Current concepts in primary sclerosing cholangitis.
To describe primary sclerosing cholangitis (PSC) and its associated complications, as well as medical and surgical treatment. A review of PSC and its associated etiopathologic factors is presented; numerous studies of agents that are used to treat patients with PSC are discussed. PSC, a slowly progressive disease that often involves autoimmune damage to the biliary tree, is frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. Long-term follow-up of patients with PSC has revealed a high incidence of colon cancer and bile duct cancer, both of which are most likely related to the chronic inflammation involving these two organs. Although PSC is an unusual disease, it is now diagnosed with approximately the same frequency as is primary biliary cirrhosis. The histopathologic evolution of PSC results in irreversible damage to bile ducts, which ultimately leads to cholestasis, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is performed. Therefore, the best chance of achieving success is to treat patients with early-stage disease rather than those with irreversible end-stage cirrhotic disease. Although several medical therapies for PSC have been evaluated, only D-penicillamine, cyclosporine, methotrexate, and, most recently, ursodeoxycholic acid have been studied in controlled clinical trials. Furthermore, several surgical therapies for PSC and its associated complications have been assessed. Currently, no therapy achieves a complete clinical, biochemical, or histologic remission in this disease. Until the etiopathogenesis of PSC is further defined, effective therapy is unlikely to be found. Thus, liver transplantation will continue to be an important therapeutic intervention for the management of patients with end-stage PSC.


Silibinin induces metabolic crisis in triple-negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications.
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment modalities and poor prognosis. Metabolic reprogramming in cancer is considered a hallmark of therapeutic relevance. Here, we report disruption of metabolic reprogramming in TNBC cells by silibinin via modulation of EGFR-MYC-TXNIP signaling. Metabolic assays combined with LC-MS-based metabolomics revealed inhibition of glycolysis and other key biosynthetic pathways by silibinin, to induce metabolic catastrophe in TNBC cells. Silibinin-induced metabolic suppression resulted in decreased cell biomass, proliferation, and stem cell properties. Mechanistically, we identify EGFR-MYC-TXNIP as an important regulator of TNBC metabolism and mediator of inhibitory effects of silibinin. Highlighting the clinical relevance of our observations, the analysis of METABRIC dataset revealed deregulation of EGFR-MYC-TXNIP axis in TNBC and association of EGFRhigh -MYChigh -TXNIPlow signature with aggressive glycolytic metabolism and poor disease-specific and metastasis-free survival. Importantly, combination treatment of silibinin or 2-deoxyglucose (glycolysis inhibitor) with paclitaxel synergistically inhibited proliferation of TNBC cells. Together, our results highlight the importance of EGFR-MYC-TXNIP axis in regulating TNBC metabolism, demonstrate the anti-TNBC activity of silibinin, and argue in favor of targeting metabolic vulnerabilities of TNBC, at least in combination with mainstay chemotherapeutic drugs, to effectively treat TNBC patients.


Pedobacter bambusae sp. nov., isolated from soil of a bamboo plantation.
An ivory white, rod-shaped, non-motile, non-spore forming, Gram-staining-negative, and aerobic bacterium designated THG-G118T, was isolated from a soil sample collected in a bamboo plantation in Seoul, Republic of Korea. The 16S rRNA gene sequence analysis revealed a clear affiliation of strain THG-G118T with the genus Pedobacter. Strain THG-G118T was found to show the closest phylogenetic relationship with Pedobacter metabolipauper WB2.3-71T with 16S rRNA gene sequence similarity of 97.3 %. The major cellular fatty acids of strain THG-G118T were identified as C16:0, C18:0, iso-C15:0 and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), and the predominant menaquinone as menaquinone MK-7. The major polar lipids were found to be phosphatidylethanolamine (PE), unidentified phospholipid and unidentified aminophospholipids. Strain THG-G118T was found to contain ceramide phosphorylethanolamine 2 (CerPE-2) and dihydrosphingosine as the major ceramide. The G+C content of the genomic DNA was found to be 41.7 mol%. DNA-DNA hybridization experiments revealed a low level of DNA-DNA relatedness (<42.5 %) between strain THG-G118T and its closest relatives. The phenotypic, chemotaxonomic and phylogenetic data showed that strain THG-G118T could be clearly distinguished from the members of the genus Pedobacter. Based on the results of a polyphasic study, a new species, Pedobacter bambusae sp. nov., is proposed. The type strain is THG-G118T (=KACC 17544T = JCM 19364T).


[Clinical and molecular genetic study of nonketotic hyperglycinemia in a Chinese family].
Nonketotic hyperglycinemia (NKH) is a rare, inborn error of metabolism. In this case report, a Chinese male infant was diagnosed with NKH caused by GLDC gene mutation. The clinical characteristics and genetic diagnosis were reported. The infant presented with an onset of early metabolic encephalopathy and Ohtahara syndrome. Both blood and urinary levels of metabolites were in the normal range. Brain MRI images indicated a poor development of corpus callosum, and a burst suppression pattern was found in the EEG. Results of target gene sequencing technology combined with multiplex ligation-dependent probe amplification (MLPA) indicated a heterozygous missense mutation of c.1786 C>T (p.R596X) in maternal exon 15 and a loss of heterozygosity of 4-15 exon gross deletions in paternal GLDC gene. These definite pathogenic mutations confirmed the diagnosis of NKH. The infant's clinical condition was not improved after treatment with adreno-cortico-tropic-hormone, topiramate and dextromethorphan, and he finally died at 4 months of age. Patients with NKH often exhibit complicated clinical phenotypes and are lack of specific symptoms. NKH could be diagnosed by metabolic screening and molecular genetic analysis.


Construction of chiral chroman scaffolds via catalytic asymmetric (4 + 2) cyclizations of para-quinone methide derivatives with 3-vinylindoles.
A catalytic asymmetric (4 + 2) cyclization of ortho-hydroxyphenyl-substituted para-quinone methide derivatives with 3-vinylindoles has been established in the presence of chiral phosphoric acid, which provides a series of chiral chroman derivatives bearing an indole moiety in generally high yields (up to 97%), and with good enantioselectivities (up to 90% ee) and moderate to good diastereoselectivities (up to 95 : 5 dr). This reaction has not only fulfilled the need of developing catalytic asymmetric (4 + 2) cyclizations of para-quinone methide derivatives with electron-rich alkenes, but also provided a useful method for constructing chiral chroman scaffolds.


Primary structure of the cDNA 5'-terminal region encoding the N-terminal domain of the rabbit muscle alpha-actinin subunit.
A number of cDNA clones have been obtained in summary encoding the N-terminal domain containing 286 amino acid residues of the rabbit skeletal muscle alpha-actinin subunit. Alpha-Actinin cDNA clones were isolated from specific cDNA libraries using the primer extension method for synthesis of the first cDNA chain. A strong stop signal for AMV reverse transcriptase in the 5'-terminal region of mRNA of alpha-actinin was found. It seems there is a G+C rich region (93% G+C nucleotides) including a continuous sequence of 23 G and C nucleotides encoding 6 glycine residues.


Remission of overt diabetes mellitus after removal of an oral epidermoid carcinoma.
This report describes a patient with an invasive epidermoid carcinoma of the tongue who presented with insulin-requiring diabetes mellitus. Fasting blood glucose was 379 mg/dl and 295 mg/dl on two successive days. The patient required 35 to 40 units of insulin per day for control. After removal of the carcinoma the insulin requirements decreased, and ultimately the insulin was stopped. One year after removal of the carcinoma, glucose and insulin levels were completely normal during an oral glucose tolerance test, demonstrating complete remission of overt diabetes mellitus.


Creation of a novel simple heat mapping method for curriculum mapping, using pathology teaching as the exemplar.
The undergraduate five-year MBChB programme at the University of Glasgow has a high volume of pathology teaching integrated into the course. The ability to better understand what pathology is taught and when, so as to build a picture of the types and depth of pathology topics covered across the programme stages is crucial, especially in a spiral curriculum. A novel method of curriculum mapping, known as curriculum heat mapping, was developed as a way to visualise where and when topics are taught, in an easier to understand format. This method involved comparing the Glasgow curriculum to a pre-determined standard of what should be taught. In this case, The Royal College of Pathologists' 'Pathology Undergraduate Curriculum' was used as a comparison of what a graduating doctor should know about pathology. Following the developed template, heat maps showcasing the range of pathology topics covered, and where they are covered, were developed for local use. These heat maps provided a clear visual representation of where and when topics are taught, and how they cluster. Heat mapping is a novel low-cost, high-input method of curriculum mapping. It requires a person to input the data which can take a long time for large curricula. There are no other upfront financial costs. It can be used in any area with a curriculum and an external or internal comparator. Examples of gold standard external comparators include validated national or international curricula. Heat mapping can help integrated, spiral curriculum programmes to identify where core topics are taught throughout their course. The heat maps themselves successfully demonstrate the required information and are easy to interpret. The process of mapping, as well as the final heat map, can yield important information. This includes information about trends within the curriculum, areas for potential improvement in sessional design and a clearer understanding of the depth to which each topic is covered in each lecture. Overall, it is a viable novel method, which has been successful locally and is easily transferable to other areas such as pharmacology.


Topiramate: new indication. Migraine prevention: best avoided.
(1) The first-line drug for prevention of migraines is propranolol: it is the most thoroughly evaluated treatment, and thus far no other drug has been found to be more effective. (2) Topiramate, an antiepileptic drug, is now also approved for migraine prevention. Only 3 out of 4 double-blind placebo-controlled trials showed that topiramate 100 mg/day was effective: on average, 46% of patients had a reduction of at least 50% in the frequency of migraines, compared to 23% of patients on placebo. Increasing the dose to 200 mg did not lead to better efficacy. (3) A double-blind trial versus propranolol failed to show that topiramate was as effective or better than propranolol. (4) Topiramate has numerous, frequent and sometimes serious adverse effects, mainly including neurosensory disorders (paraesthesias, language disorders, confusion) and gastrointestinal disturbances. (5) Topiramate treatment costs nearly 5 times more than propranolol. (6) In practice, the adverse effects of topiramate outweigh its efficacy in the prevention of migraine attacks.


The Age-Dependent Role of Th22, Tc22, and Tc17 Cells in the Severity of Pneumonia in COVID-19 Immunopathogenesis.
Coronavirus disease 2019 (COVID-19) has clinical manifestations ranging from mild symptoms to respiratory failure, septic shock, and multi-organ failure. Lymphocytes are divided into different subtypes based on their cytokine production pattern. In this study, we investigated the role of cytokine expressions of CD4+ T (T helper [Th]1, Th2, Th17, Th22) and CD8+ T cell subtypes (T cytotoxic [Tc]1, Tc2, Tc17, Tc22) in the pathogenesis of COVID-19. Peripheral blood mononuclear cells (PBMCs) were extracted with Ficoll by density gradient centrifugation from blood samples of 180 COVID-19 patients (children and adults) and 30 healthy controls. PBMCs were stimulated with PMA and Ionomycin and treated with Brefeldin A in the fourth hour, and a 10-colored monoclonal antibody panel was evaluated at the end of the sixth hour using flow cytometry. According to our findings, the numbers of Th22 (CD3+, CD4+, and interleukin [IL]-22+) and Tc22 (CD3+, CD8+, IL-22+) cells increased in adult patients regardless of the level of pneumonia (mild, severe, or symptom-free) as compared with healthy controls (p < 0.05). In addition, the number of Tc17 (CD3+, CD8+, and IL-17A+) cells increased in low pneumonia and severe pneumonia groups compared with the healthy controls (p < 0.05). Both IL-22 and IL-17A production decreased during a follow-up within 6 weeks of discharge. Our findings suggest that the increase in only IL-22 expressed Tc22 cells in the 0-12 age group with a general symptom-free course and higher levels of Th22 and Tc22 in uncomplicated adult cases may indicate the protective effect of IL-22. On the contrary, the association between the severity of pneumonia and the elevation of Tc17 cells in adults may reveal the damaging effect of IL-22 when it is co-expressed with IL-17.


Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.
We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG(OE)), which results in an increase in liver glycogen. When fed a high-fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG(OE) mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG(OE) animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and β-hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.


DiLeuPMP: A Multiplexed Isobaric Labeling Method for Quantitative Analysis of O-Glycans.
As one of the most important post-translational modifications, glycosylation plays a pivotal role in many essential physiological functions, including cell recognition, signaling, and immune response. Thus, various qualitative and quantitative analytical strategies for glycomic profiling have been developed in recent decades. However, while extensive efforts have been devoted to the analysis of N-glycans, high-throughput quantitative analysis of O-glycans is often overlooked and underexplored. This is partially due to the lack of a universal enzyme for the release of O-glycans from the protein backbone. Furthermore, the traditional chemical releasing method suffers from severe side reactions and involves tedious sample preparation procedures. Here, a multiplexed isobaric labeling method enabled by N,N-dimethyl leucine containing pyrazolone analogue (DiLeuPMP) is introduced. This method combines the release and labeling of O-glycans in a one-pot reaction and achieves accurate MS2-based relative quantification with the ability to process four samples at a time. The method has been applied to core-1 O-glycan standard and three glycoproteins first, and the results demonstrated its validity. Following this proof-of-principle demonstration, we analyzed more complex biological specimen using human serum samples. Overall, this method provides an effective and reliable approach for the profiling and high-throughput quantitative analysis of O-glycans in complex samples.


Focal Stroke in the Developing Rat Motor Cortex Induces Age- and Experience-Dependent Maladaptive Plasticity of Corticospinal System.
Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a "maladaptive" strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.


Prioritizing the Risk Factors of Severe Early Childhood Caries.
Severe early childhood caries remains the most common chronic disease affecting children. The multifactorial etiology of caries has established a controversy about which risk factors were more significant to its development. Therefore, our study aimed through meticulous statistical analysis to arrange the "well agreed upon" common risk factors in order of significance, to aid the clinician in tailoring an adequate preventive program. The study prioritized or reshuffled the risk factors contributing to severe early childhood caries and placed them in the order of their significance as follows: snacking of sugary food several times a day, increased number of siblings to three or more, night feeding, child self-employed brushing, mother's caries experience, two siblings, on demand feeding, once/day sugary food, sharing utensils, one sibling, male gender, father's education, late first dental visit, brushing time, mother's education, no dental visit, decreased brushing frequency, and no night brushing.


[Review of the fluorometric determination of urinary estrogens].
The main methods for aisolation, purification and quantification of human urine estrogens are described. The authors also analyze the historical evolution of the methods for assessing estrogens in women's urine during the menstrual cycle and during pregnancy, particularly they stress the importance of the evolution in automatic methods.