[Evaluation of estrogenicity of sewage samples from Beijing, China].
The recombinant yeast estrogen screen (YES) was used to evaluate the estrogenic activities of sewage samples from every step of three sewage treatment plants (STPs) in Beijing, China. Meanwhile, eight target endocrine-disrupting compounds (EDCs) in corresponding sewage samples were simultaneously analyzed by GC/MS system to further elucidate the variations of their estrogenic activities. The results indicated that estrogenic activities could be considerably reduced by STPs with the rate of 82.2%-97.0%. However,they were still detected in the effluent samples with the values of EEQs (expressed as E2 equivalents) 2.6-16.0 ng/L. In addition,STPs could not completely remove the target EDCs according to GC/MS analysis. The average concentration of 17alpha-E2 in the effluent was the lowest with the value of 13.5 ng/L, and the concentration of BPA (106.4 ng/L) was the largest. The estrogenic activities of effluent samples were mainly composed of steroid estrogens. Consequently, potential environmental risk can be caused by the discharge of effluents from STPs. How to effectively remove steroid estrogens during sewage treatment is, therefore, of a major concern.


Individual Hydrogen-Bond Strength QSPR Modelling with ISIDA Local Descriptors: a Step Towards Polyfunctional Molecules.
Here, we introduce new ISIDA fragment descriptors able to describe "local" properties related to selected atoms or molecular fragments. These descriptors have been applied for QSPR modelling of the H-bond basicity scale pKBHX , measured by the 1 : 1 complexation constant of a series of organic acceptors (H-bond bases) with 4-fluorophenol as the reference H-bond donor in CCl4 at 298 K. Unlike previous QSPR studies of H-bond complexation, the models based on these new descriptors are able to predict the H-bond basicity of different acceptor centres on the same polyfunctional molecule. QSPR models were obtained using support vector machine and ensemble multiple linear regression methods on a set of 537 organic compounds including 5 bifunctional molecules. They were validated with cross-validation procedures and with two external test sets. The best model displays good predictive performance on a large test set of 451 mono- and bifunctional molecules: a root-mean squared error RMSE=0.26 and a determination coefficient R(2) =0.91. It is implemented on our website (http://infochim.u-strasbg.fr/webserv/VSEngine.html) together with the estimation of its applicability domain and an automatic detection of potential H-bond acceptors.


Modeling neural tube defects in the mouse.
Neural tube defects (NTDs) are among the most common structural birth defects observed in humans. Mouse models provide an excellent experimental system to study the underlying causes of NTDs. These models not only allow for identification of the genes required for neurulation, they provide tractable systems for uncovering the developmental, pathological and molecular mechanisms underlying NTDs. In addition, mouse models are essential for elucidating the mechanisms of gene-environment and gene-gene interactions that contribute to the multifactorial inheritance of NTDs. In some cases these studies have led to development of approaches to prevent NTDs and provide an understanding of the underlying molecular mechanism of these therapies prevent NTDs.


ST-segment abnormalities and premature complexes are predictors of new-onset atrial fibrillation: the Niigata preventive medicine study.
Left ventricular hypertrophy is a known risk factor for atrial fibrillation (AF). However, it is not well understood whether other electrocardiogram abnormalities are associated with development of AF. This was a community-based cohort study based upon a database of annual health examinations. We included 63,386 subjects aged > or = 50 years, without baseline AF (including atrial flutter), structural heart disease, or heart failure, who completed the annual examination during a 10-year follow-up period (1991-2002). The electrocardiographic risk factors for AF were studied in the subjects. Atrial fibrillation developed in 873 subjects. Age, male sex, body mass index, hypertension, systolic and diastolic blood pressure, and diabetes were significant risk factors for the development of AF. In multivariable logistic regression analysis adjusted for these risk factors, electrocardiographic left ventricular hypertrophy (odds ratio [OR], 1.43), ST-segment abnormality without left ventricular hypertrophy (OR, 1.89), and the presence of premature complexes during a 10-second recording (OR, 2.89) were significantly associated with AF, whereas either right (OR, 0.84) or left bundle branch block (OR, 0.96) was unrelated. The risk for AF increased progressively with the severity of both ST-segment change and premature complexes. ST-segment abnormality and comparably high-frequency premature complexes were each associated with increased risk for the development of AF. These electrocardiographic findings may be useful to stratify high-risk subjects for new-onset AF.


Aspects of the ecology of Carabidae (Coleoptera) from woodlands polluted by heavy metals.
The carabid faunas of six woodlands at varying distances from a source of heavy metal pollution were studied. Concentrations of zinc, lead, cadmium and copper were determined in three surface layers at each wood. Whereas no gross effects of pollution on populations were identified, some differences relating to the ecology and life histories of the animals were found. The numbers of individuals and numbers of species of Carabidae at each site were not significantly correlated to metal concentration. However, species diversities (Shannon Weiner H') were. Later dates of median capture of total Carabidae were found in the sites nearest to the pollution source. This also occurred with a common species, Nebria brevicollis. At the most polluted site this species also showed an absence of summer diapause. This may be relatd to scarcity of prey. Negative correlations of numbers of spring breeders with metal concentration but positive correlations of numbers of spring breeders with in all the soil layers. The sites were significantly different in the relative distributions of individuals in each of four size categories.


Giving away free nicotine medications and a cigarette substitute (Better Quit) to promote calls to a quitline.
This article presents results from two population-based promotions for free cessation products used to induce smokers to call the New York State Smokers'. The first promotion was a press announcement urging smokers to call the quitline to get a voucher for a free 2-week supply of nicotine patches or gum (nicotine replacement therapy [NRT]). The second promotion involved comparing response to two newspaper advertisements for the quitline, one of which offered a free stop smoking guide and one that offered the guide plus a free stop smoking aide called Better Quit (BQ). Responses to each promotion were monitored by tracking the call volume to the quitline-before, during, and after each of the promotions. The NRT voucher promotion increased median call volume 25-fold compared to prepromotion levels, whereas the BQ newspaper advertisement increased median call volume 2-fold compared to a newspaper advertisement for the quitline, which did not offer BQ. A random sample of 732 smokers who received the free NRT voucher were followed up 4 to 6 months later to determine their use of NRT and smoking behavior. Embedded within this follow-up study was a randomized experiment in which half the smokers were mailed a quit kit with BQ included and the other half received just the quit kit. Seventy percent of follow-up survey respondents said that they had redeemed the NRT voucher and used the medication to try to quit smoking. Twenty-two percent reported they were no longer smoking, compared with the 12 percent among a comparison group of quitline callers who had not received the free NRT voucher (odds ratio = 1.77; 95% confidence interval: 1.17-2.68). There was no difference in quit rates between those that were sent the BQ cigarette substitute and those that did not get the BQ. This study shows that offering a free 2-week voucher for NRT is a cost-effective method to increase calls to a stop smoking quitline and may also increase the odds of quitting for those who get the free NRT.


[Professional Burnout Syndrome of intensive care physicians from Salvador, Bahia, Brazil].
Describe prevalence of the Burnout syndrome in intensive care physicians of Salvador, associated to demographic data and aspects of the work environment (psychological demand and job control). This cross sectional study has investigated the association between work conditions and Burnout Syndrome in a population of 297 Intensive Care Physicians from Salvador, Bahia, Brazil. An individual, self-report questionnaire evaluated the physicians' psychological aspects of work, using the demand-control model (Job Content Questionnaire) and their mental health, using the Maslash Burnout Inventory (MBI). The study found work overload,a high proportion of on duty physicians and low income for the hours worked. Prevalence of the Burnout Syndrome was 7.4% and it was more closely associated with aspects of the job's psychological demand than with its control. Physicians under great stress (high demand and low control) presented prevalence of the Bornout Syndrome 10.2 times higher than those under low stress (low demand and high control) jobs.


[The acceleration of remission after exacerbation of chronic suppurative otitis media following functional-reconstructive operations on the middle ear].
This study had the objective to enhance the efficacy of the surgical treatment of the patients presenting with chronic suppurative otitis media by means of reduction of the time needed to achieve persistent remission of the disease in the framework of a complex of therapeutic and rehabilitative measures making possible the surgical intervention on the middle ear regardless of the activity of the inflammatory process and its severity. Sixty five patients with chronic suppurative otitis media were examined and treated to estimate the clinical efficiency of the proposed complex of therapeutic and rehabilitative measures. It is maintained that this complex allows to achieve the positive results of reconstructive and restorative surgery without waiting for the development of long-term remission.


Extracting gait parameters from raw electronic walkway data.
Spatiotemporal gait parameters are very important for the detection of gait impairments and associated conditions. Current methods to measure such parameters, e.g. electronic walkways or force plates, are costly and can only be used in a laboratory. The new generation of raw data accelerometers might be a cheap and flexible alternative. We conducted a small feasibility study with 50 subjects from the KORA-Age project exploring the output of GAITRite and Actigraph GT3X. We open-sourced a package to extract and process raw data from GAITRite. The most promising location for the accelerometer seems to be at the ankle. The use of accelerometers showed to be simple and reliable, indicating that they can be used in daily life to extract gait parameters.


Effect of pyrazole on ethanol metabolism in ethanol-tolerant rats.
Adult male rats were pair-fed liquid diets, providing 37% of calories as ethanol or sucrose, for 1 month. Alcohol dehydrogenase (ADH) activity in the cytosol fractions of liver homogenates from the two groups did not differ with respect to total activity per 100 g body weight, Km for ethanol, or Ki for pyrazole. Other rats, fed in the same way, were fasted for 18-24 H, then given an intraperitoneal injection of pyrazole followed 1 h later by an injection of ethanol, 3g/kg. Blood alcohol curves showed an unexplained slower rise to maximum level in the chronic alcohol group. Both groups showed a period of several hours in which the blood alcohol stayed at the respective maximum concentrations, which were higher in the control group. After 7-8h the alcohol concentration began to fall in both groups, significantly more rapidly in the chronic alcohol-fed animals. A kinetic analysis shows that the results are adequately explained by the known effects of pyrazole on the ADH-mitochondrial system. The results are interpreted as evidence against the function of any microsomal ethanol oxidizing system in vivo.


Abnormal heart rate variability reflecting autonomic dysfunction in brainstem infarction.
Brainstem infarctions frequently cause disturbances of cardiovascular and other autonomic functions, but the pathophysiologic mechanisms of these prognostically unfavourable complications are not well-known. In order to evaluate the effects of ischemic brainstem infarction on autonomic cardiac regulation, we analyzed the power spectrum of heart rate variability in 15 consecutive patients with brainstem infarction and in 15 age- and sex-matched healthy control subjects. The components of the power spectrum which reflect quantitatively both sympathetic and parasympathetic cardiovascular regulatory functions were measured from 24-hour electrocardiogram in the acute phase and at 1 month and 6 months after the infarction. All the measured components of heart rate variability, i.e., total power (p < 0.01), very-low-frequency power (p < 0.001), low-frequency power (p < 0.01), and high-frequency power (p < 0.05), were significantly lower in the patients with medullary brainstem infarction than in the control subjects in the acute phase of the infarction. By 6 months, these abnormalities had been reversed. On the contrary, heart rate variability in pontine brainstem infarct patients did not differ significantly from that in the control subjects. These results suggest that brainstem infarction located in the medulla oblongata causes cardiovascular autonomic dysregulation manifesting as impaired heart rate variability. Medullary brainstem infarction seems to cause both sympathetic and parasympathetic dysfunction, which may contribute to the occurrence of cardiac complications in stroke.


Local circuit properties underlying cortical reorganization.
Peripheral denervation has been shown to cause reorganization of the deafferented somatotopic region in primary somatosensory cortex (S1). However, the basic mechanisms that underlie reorganization are not well understood. In the experiments described in this paper, a novel in vivo/in vitro preparation of adult rat S1 was used to determine changes in local circuit properties associated with the denervation-induced plasticity of the cortical representation in rat S1. In the present studies, deafferentation of rat S1 was induced by cutting the radial and median nerves in the forelimb of adult rats, resulting in a rapid shift of the location of the forepaw/lower jaw border; the amount of the shift increased over the times assayed, through 28 days after denervation. The locations of both borders (i.e., original and reorganized) were marked with vital dyes, and slices from the marked region were used for whole-cell recording. Responses were evoked using electrical stimulation of supragranular S1 and recorded in supragranular neurons close to either the original or reorganized border. For each neuron, postsynaptic potentials (PSPs) were evoked by stimulation of fibers that crossed the border site (CB stim) and by equivalent stimulation that did not cross (NCB stim). Monosynaptic inhibitory postsynaptic potentials (IPSPs) were also examined after blocking excitatory transmission with 15 microM CNQX plus 100 microM DL-APV. The amplitudes of PSPs and IPSPs were compared between CB and NCB stimulation to quantify effects of the border sites on excitation and inhibition. Previous results using this preparation in the normal (i.e., without induced plasticity) rat S1 demonstrated that at a normal border both PSPs and IPSPs were smaller when evoked with CB stimulation than with NCB stimulation. For most durations of denervation, a similar bias (i.e., smaller responses with CB stimulation) for PSPs and IPSPs was observed at the site of the novel reorganized border, while no such bias was observed at the suppressed original border site. Thus changes in local circuit properties (excitation and inhibition) can reflect larger-scale changes in cortical organization. However, specific dissociations between these local circuit properties and the presence of the novel border at certain durations of denervation were also observed, suggesting that there are several intracortical processes contributing to cortical reorganization over time and that excitation and inhibition may contribute differentially to them.


Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1.
Deficient angiogenesis after ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in peripheral arterial disease, maladaptive changes in VEGF ligand/receptor expression could account for impaired angiogenesis in DM. Skeletal muscle from diet-induced, type 2 diabetic (DM) and age-matched normal chow (NC)-fed mice was collected at baseline and 3 and 10 days after hindlimb ischemia and analyzed for expression of VEGF (n=10 per group), full-length VEGF receptor (VEGFR)-1, soluble VEGFR-1, and markers of downstream VEGF signaling (n=20 per group) using ELISA, reverse transcriptase-polymerase chain reaction, and Western blots. In the absence of ischemia, DM mice had increased VEGF (NC versus DM: 26.6+/-2.6 versus 53.5+/-8.8 pg/mg protein; P<0.05), decreased soluble and membrane-bound VEGFR-1 (NC versus DM: 1.44+/-0.30 versus 0.85+/-0.08 and 1.03+/-0.10 versus 0.72+/-0.10, respectively; P<0.05), decreased phospho-AKT/AKT and phospho-endothelial NO synthase/endothelial NO synthase (NC versus DM: 0.76+/-0.2 versus 0.38+/-0.1 and 0.36+/-0.06 versus 0.25+/-0.04, respectively; P<0.05), and no change in VEGFR-2. After ischemia, both DM and NC had comparable increases in VEGF-A. VEGFR-1 and soluble VEGFR-1 expression increased in both groups, but the fold increase was significantly greater in DM. These data demonstrate that soluble VEGFR-1, an angiogenesis inhibitor, is regulated in skeletal muscle by type 2 DM and ischemia. In the absence of ischemia, despite reductions in both soluble VEGFR-1 and VEGFR-1, VEGF ligand signaling is lower in DM compared with controls. After ischemia, maladaptive upregulation of these receptors further reduces the capacity of VEGF to induce an angiogenic response, which may provide a novel target for therapy.


Genetic screening of THAP1 in primary dystonia patients of India.
Primary Dystonia is a common movement disorder manifested by dystonic symptoms only. DYT6, a major genetic factor, plays a significant role in primary pure dystonia pathogenesis. In this study we analyzed THAP1 (DYT 6) gene in primary pure dystonia patients, which has been widely studied in other populations but not in Indians. The study cohort contained 227 index primary pure dystonia patients with the involvement of cervical region and 254 neurologically control individuals collected from East Indian population. All three exons of THAP1 and their flanking sequences, including exon-intron boundaries, were screened by PCR, DNA sequencing and/or RFLP analysis. A total of three nucleotide variants were detected, which include a reported missense mutation (c.427 A>G; p.Met143Val) in a juvenile onset generalized dystonia patient, a novel frameshift deletion mutation (c.208-209 ΔAA; p.K70VfsX15) in a juvenile onset cervical dystonia patient and a rare variant in 3' UTR of THAP1 (c.*157 T>C) in an adult-onset blepharospasm patient. In addition, two SNPs (rs71521601 and rs111989331) were detected both in the patients and controls with the major allele of the latter being significantly over represented in the patients. Our study suggests that the THAP1 is likely to have a causative role in the pathogenesis of Indian primary pure dystonia patients. Though the phenotypic spectrum is extensively diverse, the cervical involvement with dystonic tremor and speech problem is common amongst the patients harboring mutations.


Distribution of cDNA for melanocortin receptor subtypes in human tissues.
Distribution of cDNA for five individual melanocortin receptor subtypes in 20 different human tissues was determined by PCR using subtype specific primers. PCR products were first visualised by agarose gel electrophoresis and ethidium bromide staining, and specific products were identified for melanocortin 1 receptor (MC1R) in pituitary and testis, for MC2R in adrenal gland, for MC3R in heart, for MC5R in adrenal gland, fat cells, kidney, leukocytes, lung, lymph node, mammary gland, ovary, pituitary, testis and uterus. The MC4R cDNA could not be detected by ethidium bromide staining. More tissues were revealed as positive when the DNA from PCR were hybridised with subtype specific radioactive probes. All the subtypes except MC4R could be detected in testis. MC4R could only be detected in pituitary. This is the first report describing the comprehensive distribution analysis of melanocortin receptor subtype cDNAs in human tissues, and provides a link between individual receptor subtype and diverse biological activities of melanocortic peptides in the respective target tissues.


PGE 2 and dibutyryl cyclic adenosine monophosphate prolong eosinophil survival in vitro.
Apoptosis represents a mechanism by which the accumulation and inflammatory potential of eosinophils in asthma might be limited. Mediators derived from the airway epithelium may influence the rate of eosinophil apoptosis. We have investigated the effects on eosinophil apoptosis of 3 mediators that are likely to be produced by the airway epithelium, namely PGE2, TNF-alpha, and nitric oxide. Peripheral blood eosinophils from healthy adult volunteers were purified by density gradient centrifugation and negative immunomagnetic selection. Eosinophils were cultured for 16 or 40 hours with PGE2 (10 nmol/L), dibutyryl cyclic adenosine monophosphate (AMP; 100 micromol/L), TNF-alpha (500 U/mL), the nitric oxide donors, S-nitroso-N-acetylpenicillamine (100 micromol/L), and 2,2;-(hydroxynitrosohydrazono)bis-ethanamine (1 mmol/L), or dibutyryl cyclic guanosine monophosphate (100 micromol/L). Control cultures consisted of untreated, IL5-treated (100 U/mL), and anti-Fas-treated (400 ng/mL) cells. Eosinophil apoptosis was assessed by flow cytometric analysis of annexin V-FITC binding to externalized phosphatidylserine, by electrophoresis of phosphorus 32 end-labeled DNA fragments, and by flow cytometric assessment of hypodiploid DNA with propidium iodide. PGE2 and cyclic AMP inhibited spontaneous eosinophil apoptosis at both 16 and 40 hours as did the PGEP2 receptor agonist, 11-deoxy PGE1, at 40 hours, but these effects were not inhibited by a protein kinase A antagonist. TNF-alpha delayed apoptosis in eosinophil cultures at 16 hours, whereas S-nitroso- N-acetylpenicillamine, 2, 2;-(hydroxynitrosohydrazono)bis-ethanamine, and cyclic guanosine monophosphate had little effect. Anti-Fas had little effect on spontaneous eosinophil apoptosis but significantly reduced the inhibitory effects of PGE2, cyclic AMP, and TNF-alpha. Assessments of apoptosis by DNA fragmentation gave similar but quantitatively less sensitive results. Inhibition of spontaneous eosinophil apoptosis by PGE2 appears to be mediated by EP2 receptors but is not protein kinase A dependent. By enhancing eosinophil survival, PGE2 may increase the proinflammatory potential of these cells in chronic asthma.


Quantized CNN: A Unified Approach to Accelerate and Compress Convolutional Networks.
We are witnessing an explosive development and widespread application of deep neural networks (DNNs) in various fields. However, DNN models, especially a convolutional neural network (CNN), usually involve massive parameters and are computationally expensive, making them extremely dependent on high-performance hardware. This prohibits their further extensions, e.g., applications on mobile devices. In this paper, we present a quantized CNN, a unified approach to accelerate and compress convolutional networks. Guided by minimizing the approximation error of individual layer's response, both fully connected and convolutional layers are carefully quantized. The inference computation can be effectively carried out on the quantized network, with much lower memory and storage consumption. Quantitative evaluation on two publicly available benchmarks demonstrates the promising performance of our approach: with comparable classification accuracy, it achieves 4 to $6 \times $ acceleration and 15 to $20\times $ compression. With our method, accurate image classification can even be directly carried out on mobile devices within 1 s.


New diarylheptanoids from the rhizomes of Dioscorea spongiosa and their antiosteoporotic activity.
Bioassay-guided fractionation of the water extract of the rhizomes of Dioscorea spongiosa led to the isolation and identification of new diarylheptanoids, diospongins A - C, together with three known lignans. Their structures, including absolute stereochemistry, were determined by analyses of NMR data, chemical conversions and CD spectrum. The isolated compounds, except for diospongin A, exerted potent inhibitory activities on bone resorption induced by parathyroid hormone in a bone organ culture system.


A novel CuZnInS quantum dot-based ECL sensing system for lysophosphatidic acid detection.
In this paper, a novel electrochemiluminescence (ECL) sensor for lysophosphatidic acid (LPA) detection was developed. LPA consists of a phosphate "head" group, a "linker" region illustrated by glycerol, and a fatty acyl chain as a lipophilic "tail". The water-soluble quaternary CuInZnS quantum dots (QDs) were modified with agmatine (AGM) molecules as an ECL luminophore. On the one hand, the guanidine groups on the QDs can capture the hydrophilic head of LPA with high selectivity. On the other hand, the electrochemically reduced graphene nanosheets (GNs) modified on the glassy carbon electrode (GCE) surface can bind the LPA lipophilic tail. As a result, the LPA-AGM-CuInZnS QDs were captured on the GNs/GCE. The ECL intensity of the system was enhanced with the increased concentration of LPA. As far as we know, it was the first report about LPA detection based on the ECL nanosensing system. The linear relationship range of LPA sensing is from 2 to 75 μmol L-1. The practicability of this ECL sensing platform had shown satisfactory results in human serum samples.


Low dose oral interferon alpha 2a in HIV-1 seropositive patients: a double-blind, placebo-controlled trial.
Low dose oral interferon alpha has been shown to be of benefit in viral disease in animals. In a double-blind, placebo-controlled trial, 177 patients seropositive for HIV-1 were randomly assigned to receive placebo or recombinant human interferon alpha 2a (rIFN alpha). Endpoints were survival, alteration of disease classification, performance, and changes in CD4+ T cell numbers. There was a trend for improved survival in the group receiving rIFN alpha at the dose of 1.0 IU/lb. The changes in disease classification or in weight were not significantly different. Performance was improved to a greater extent (p=0.1) in the patients who received the two higher rIFN alpha dosages (1.0 IU/lb and 10.0 IU/lb) at 6 months. In addition, the CD4+ T cell count was improved only in the 1.0 IU/lb dose treatment group at 6 months. Treatment with low dose oral interferon at 1.0 IU/lb was associated with improved CD4+ T cell count, performance and a trend toward enhanced survival in HIV seropositive patients. These differences were, however, not statistically significant. A larger study, with better return rate, will be needed to determine whether low dose, oral interferon alpha is actually beneficial for these patients.


Force transmission at cell-cell and cell-matrix adhesions.
All cells are subjected to mechanical forces throughout their lifetimes. These forces are sensed by cell surface adhesion receptors and trigger robust actin cytoskeletal rearrangements and growth of the associated adhesion complex to counter the applied force. In this review, we discuss how integrins and cadherins sense force and transmit these forces into the cell interior. We focus on the complement of proteins each adhesion complex recruits to bear the force and the signal transduction pathways activated to allow the cell to tune its contractility. A discussion of the similarities, differences, and crosstalk between cadherin- and integrin-mediated force transmission is also presented.


Pluripotency network in embryonic stem cells: maybe Leibniz was right all along.
The transcription factors Tcf3 and Nanog regulate many genes in embryonic stem cells, but according to two reports in this issue of Cell Stem Cell (Festuccia et al., 2012, Martello et al., 2012), only one, Esrrb, encoding an orphan nuclear hormone receptor, truly matters in the maintenance of self-renewal.


Neuropathologic features of idiopathic respiratory distress syndrome.
Evaluation of the neuropathologic alterations occurring in 170 consecutive autopsies in premature infants dying of the idiopathic respiratory distress syndrome (IRDS) reveals two large groups, hemorrhagic and nonhemorrhagic. Hemorrhages occurred in all possible sites and formed the single largest group. Such hemorrhages appeared to be related to the early death of many premature infants. The nonhemorrhagic group was quite variable, with the largest category of associated lesions being periventricular leukomalacia, the frequency of which increased with increasing age. We suggest that the nonhemorrhagic group may be an important factor in the morbidity of survivors.


Impact of acute sleep restriction on cerebral glucose metabolism during recovery non-rapid eye movement sleep among individuals with primary insomnia and good sleeper controls.
Restricting time in bed improves insomnia symptoms, but the neural mechanisms for this effect are unknown. Total and partial acute sleep restriction may be useful paradigms for elucidating these effects. We examined the impact of acute sleep restriction on cerebral glucose metabolism during non-rapid eye movement (NREM) sleep in individuals with primary insomnia (n = 17) and good sleep (n = 19). Participants underwent [18F]fluorodeoxyglucose positron emission tomography scans during baseline and recovery NREM sleep following one night of partial or total sleep restriction. We compared group differences in baseline-recovery changes, as well as main effects of group and condition (baseline vs. recovery NREM sleep), for relative regional cerebral metabolic rate for glucose (rCMRglc), whole-brain glucose metabolism, and sleep quality. Relative rCMRglc was significantly lower during recovery NREM sleep compared to baseline in the left frontoparietal cortex, medial frontal cortex, posterior cingulate cortex, and thalamus, with no significant group differences. Good sleepers, but not insomnia patients, had lower whole-brain glucose metabolism during recovery NREM sleep compared to baseline. Acute sleep restriction improved sleep quality in individual with insomnia. Subgroup analyses including only participants who underwent partial sleep restriction yielded the same pattern of findings. Individuals with insomnia and good sleepers showed similar relative rCMRglc responses to acute sleep restriction. Brain regions showing the greatest baseline-recovery changes in both groups included regions previously shown to have smaller sleep-wake differences in patients with primary insomnia. Acute sleep restriction, and by extension sleep restriction therapy, may impact regional metabolic alterations that characterize insomnia.


The neurology of poverty.
An intellectual deficit is known to exist in populations where extreme poverty is rife and is thus seen extensively in the lower socio-economic strata of underdeveloped nations. Poverty is a complex entity whose sociological and economic indicators often bear little relevance to the biological agents which can affect the central nervous system. An attempt is made to express poverty in terms of identifiable defects, physiological in nature. Thus adverse socio-economic factors are converted into specific biological entities which, though necessary for adequate development of the brain, are restricted where there is poverty. A number of causative deficiencies, including nutritional, visual, auditory, tactile, vestibular, affective, and other stimuli are postulated. These interact and potentiate one another. Each is capable of an independent action on the brain and examples are given of some sensory deprivations as well as malnutrition and their possible mechanism of action. If the various deficiencies can independently harm the brain, then a number of separate specific functions should be affected; examples are offered. The nature of this intellectual deficit is probably a non-fulfillment of genetic potential of certain specific functions of the brain, which may exhibit limited variations between one community and another, depending on cultural differences. The deleterious effect of this intellectual impairment is seen most clearly in figures of school desertion, for example in Latin America. Analogous data for adults is scarce.


Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.


Cardiovascular activity of aromatic guanidine compounds.
A series of aromatic guanidines and several 1-phenylbiguanides was prepared and tested for cardiovascular (CV) effects in anesthetized dogs measuring heart rate, blood pressure, carotid artery blood flow, and myocardial force changes. The predominant CV effect at minimally effective dose was vasoconstriction unassociated with cardiac stimulation. The structure-activity relationships of the compounds were discussed comparing their structural similarities to the beta-phenylethylamines. The most potent members of the series were phenylguanidines substituted in the 3 and 4 positions on the aromatic nucleus with hydroxy or chloro groups. Preliminary mechanism studies indicated that the 3,4-dihydroxyphenylguanidines act at least partially by a direct alpha-adrenergic mechanism


Therapeutic failure of primaquine and need for new medicines in radical cure of Plasmodium vivax.
Primaquine has been the drug of choice for the prevention of Plasmodium vivax relapse for more than 60 years. Primaquine tolerant strain of P. vivax was identified in 1944. Significant mortality and disease burden of P. vivax calls for the need of new drugs. Primaquine resistance is a complex issue, as the mechanism of resistance is not clear. Direct evidence of resistance to primaquine by hypnozoites has not yet been shown. There are some reports detailing risk of primaquine resistance in specific regions, but the overall distribution of primaquine resistance in P. vivax-infected people is largely unknown. Confounding factors contribute to treatment failures; such as inadequate doses, inappropriate dosing intervals, risk of reinfection, combinations with blood schizontocidals, and compliance. Therefore, primaquine resistance needs to be addressed along with additional important confounding factors. Tafenoquine is the most studied drug in replacing primaquine for the radical cure of P. vivax malaria. It has comparable efficacy with primaquine. The potential advantage of tafenoquine is better compliance with a single dose regimen. Rational use of primaquine can secure its effectiveness, but it is essential in the future to have better or similar alternatives to treat P. vivax.


A comparison of the body height of the Israeli-born and immigrants to Israel.
This paper reports a study of body height in the adult Jewish population of Israel, comparing native-born with immigrant groups. The sample tested included 1,411 men and 961 women, all clinically healthy according to the results of multiphasic screening. The phenomenon observed in other immigration-absorbing countries also holds for Israel: native Israelis are significantly taller than their immigrant counterparts. The findings were verified over different age and working activity strata, and thus may be taken to reflect the influence of better socioeconomic and environmental conditions on the bodily development of those born in Israel.


Efficacy of steroid pulse therapy in combination with mizoribine following tonsillectomy for immunoglobulin A nephropathy in renally impaired patients.
The long-term prognosis of immunoglobulin A nephropathy is poor. Treatment is intended to achieve complete remission in the early stage or to preserve renal function in the advanced stages. In Japan, aggressive steroid pulse therapy following tonsillectomy (tonsillectomy-pulse therapy) has recently been used to treat early IgA nephropathy and has achieved favorable outcomes. However, steroid doses are sometimes limited because of adverse reactions s and the efficacy of tonsillectomy-steroid pulse therapy has not been established in patients with renal dysfunction. In our current treatment protocol, the total steroid dose has been significantly reduced through the use of the immunosuppressant mizoribine in combination with tonsillectomy-steroid pulse therapy for the treatment of active IgA nephropathy in patients with renal impairment. The subjects were 18 patients with active IgA nephropathy who were younger than 70 years and had an estimated glomerular filtration rate ≥20 and <60 mL/min/1.73 m(2). After giving informed consent, the patients underwent bilateral tonsillectomy. One week later, intravenous methylprednisolone pulse therapy (500 mg/day) was administered for 3 days, followed by oral prednisolone in combination with mizoribine (100 to 150 mg/day). A renin-angiotensin system inhibitor was used before tonsillectomy in all cases. One year after tonsillectomy, the safety of this protocol and its effects on hematuria, proteinuria, and the progression of renal dysfunction were assessed. The mean patient age was 48.4 years, and the mean time from disease onset to tonsillectomy was 8.4 years. After 1 year, urinary protein had decreased (1.80 ± 1.36 to 0.47 ± 0.75 g/g · Cr) in all cases but 1 and had resolved completely in 38.9% of cases. Hematuria had decreased in all cases and had resolved completely in 61.1% of cases. The estimated glomerular filtration rate also improved in all cases and the mean increased significantly from 42.4 ± 11.9 to 50.1 ± 15.9 mL/min/1.73 m(2). No serious complications were found during follow-up. Steroid acne that required treatment occurred in 2 cases (11.1%) but was transient and mild. Steroid pulse therapy in combination with mizoribine following tonsillectomy is effective in improving urinary findings and preserving renal function in the treatment of IgA nephropathy, which remained active in patients with renal impairment (estimated glomerular filtration rate ≥20 and <60 mL/min/1.73 m(2)).


Increasing age is associated with faster progression to neoplasms but not opportunistic infections in HIV-infected homosexual men.
To characterize the associations of age and progression rates to AIDS-defining neoplasms and opportunistic infections (OI) in HIV-infected homosexual men. Data from 407 homosexual men with documented dates of HIV seroconversion participating in cohort studies from four geographic locations were merged. Kaplan-Meier and Cox proportional hazards analyses were conducted with respect to the association of age with time from seroconversion to the first AIDS-defining neoplasm and OI. Among the 407 participants, 139 (34%) were diagnosed with AIDS; 45 (11%) with neoplasms and 90 (22%) with OI. Older age at seroconversion was significantly associated with faster progression to neoplasms, but not to OI. For each 10-year increase in age the risk for neoplasms increased 1.65-fold [95% confidence interval (CI), 1.12-2.43], after adjustment for clinical treatments. For OI this risk estimate was 0.98 (95% CI, 0.72-1.34). Increasing age is associated with faster progression to AIDS-defining neoplasms, but not with progression to OI. This has not been previously reported and may explain conflicting results in other studies among homosexual men that considered AIDS as a single entity. Our findings suggest that age and AIDS manifestations should be considered, particularly in the context of natural history studies, clinical trials and mathematical modelling.


Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner.
Chronic infection and inflammation of the airways is a hallmark of cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The response of the CF airway epithelium to the opportunistic pathogen Pseudomonas aeruginosa is characterized by altered inflammation and apoptosis. In this study, we examined innate immune recognition and epithelial responses at the level of the gap junction protein connexin43 (Cx43) in polarized human airway epithelial cells upon infection by PAO1. We report that PAO1 activates cell surface receptors to elicit an intracellular signaling cascade leading to enhancement of gap junctional communication. Expression of Cx43 involved an opposite regulation exerted by JNK and p38 MAPKs. PAO1-induced apoptosis was increased in the presence of a JNK inhibitor, but latter effect was prevented by lentiviral expression of a Cx43-specific short hairpin RNA. Moreover, we found that JNK activity was upregulated by pharmacological inhibition of CFTR in Calu-3 cells, whereas correction of a CF airway cell line (CF15 cells) by adenoviral expression of CFTR reduced the activation of this MAPK. Interestingly, CFTR inhibition in Calu-3 cells was associated with decreased Cx43 expression and reduced apoptosis. These results indicate that Cx43 expression is a component of the response of airway epithelial cells to innate immune activation by regulating the survival/apoptosis balance. Defective CFTR could alter this equilibrium with deleterious consequences on the CF epithelial response to P. aeruginosa.


The utility of genetic testing in neuromuscular disease: A consensus statement from the AANEM on the clinical utility of genetic testing in diagnosis of neuromuscular disease.
The aim of this consensus statement is to provide a recommendation from AANEM experts on the clinical utility of genetic testing. It is not meant to recommend or endorse any specific genetic testing methodology or algorithm. The AANEM Professional Practice Committee reached a consensus based on expert opinion on the utility of genetic testing in neuromuscular diseases and made recommendations on factors that physicians and patients should consider when deciding whether to proceed with such testing. Despite the costs of genetic testing, these tests can be both valuable and beneficial in the diagnosis and treatment of neuromuscular diseases in many situations. The AANEM believes that performing genetic testing to arrive at a specific molecular diagnosis is a critical step in providing high-quality care to neuromuscular patients. The cost of testing should not be a deterrent, as there are important clinical, safety, psychosocial, and research benefits. Muscle Nerve 54: 1007-1009, 2016.


Multicentric study on total pancreatectomies.
Total pancreatectomy (TP) is an uncommon operation, with indications that have not been clearly defined and non-standardized postoperative results. We present a national multicentric study on TP and a comparison with the existing literature METHODS: A prospective observational study using data from the national registry of patients after pancreaticoduodenectomy and TP performed for any indication during the study period: January 1 to December 31, 2015 RESULTS: 1016 patients were included from 73 hospitals, 112 of whom had undergone TP. The percentage of TP from the total number of cases was 11%. The mean age was 63.5 years, and 57.2% were males. The most frequently suspected radiological diagnosis was pancreatic cancer (58/112 cases). The most common TP technique was "mesentery artery first" (43/112 cases). Venous resections were performed in 23 patients (20.5%). The percentage of postoperative complications within 90 days was 50%, but major complications (>IIIA) were only 20.7%. The overall 90-day mortality was 8% (9 patients). The average stay was 20.7 days. The 3most frequent definitive histological diagnoses were: adenocarcinoma of the pancreas, intraductal papillary mucinous neoplasm and chronic pancreatitis. The R0 rate was 67.8%. This study shows that the morbidity and mortality results of TP in Spain are similar or superior to previous publications. More precise TP studies are necessary, focused on specific complications such as endocrine insufficiency.


Genotypes of hepatitis B virus in Central Anatolia, Kayseri, Turkey.
To investigate the distribution of hepatitis B virus (HBV) genotypes among patients with chronic hepatitis B in Kayseri, Turkey. The study took place in the Department of Microbiology, Erciyes University, Kayseri, and Iontek Laboratory, Istanbul, Turkey, from January 2005 to October 2007. One hundred and ten patients with chronic hepatitis B were included in this study. Hepatitis B virus DNA in sera were investigated by using the real-time polymerase chain reaction. Viral DNA was extracted from 200 uL of serum using the QIAamp DNA minElute kit (Qiagen, Hilden, Germany). Reaction mixture was prepared by Fluorion HBV QNP 2.0 ( Iontek, Istanbul, Turkey). Genotype D was detected in 107 of 110 (97.2%) patients, however, genotyping failed in 3 patients (2.7%). No other genotypes were found. The vast majority of Turkish patients with chronic hepatitis B have genotype D.


[Development of tumor targeting PHBHHx nanoparticles by PhaP mediated immobilization of EGFR-targeting peptide].
PHA granule binding protein phasin (PhaP) has a high affinity for hydrophobic materials and can bind to hydrophobic polymers via strong hydrophobic interaction. In this study, an EGFR-targeting peptide (ETP) was fused with PhaP and the fusion protein ETP-PhaP was produced in recombinant Escherichia coli BL21 (DE3) (pPI-ETP-P) and then purified by Ni affinity purification. The tumor targeting PHBHHx nanoparticles were developed based on PhaP mediated ETP immobilization and the cellular uptake of the ETP-PhaP modified PHBHHx NPs and none modified PHBHHx NPs by cervical cancer cell lines SiHa (EGFR over expressed) and CaSKi (EGFR low expressed) were analyzed. The purified ETP-PhaP could be adsorbed onto the hydrophobic surface of PHBHHx NPs. The ETP-PhaP modified PHBHHx NPs could target to EGFR over expressed cervical cancer cells SiHa more efficiently than to the EGFR low expressed CaSKi cells. These results demonstrated the advantage in effectiveness and convenience of PhaP mediated ETP adsorption on PHBHHx nanoparticles, providing a novel strategy for hydrophobic nanocarrier surface modification.


Histological and histochemical characterisation of the equine soft palate muscles.
Dysfunction of the muscles is implicated in the pathogenesis of intermittent dorsal displacement of the soft palate (DDSP) in exercising horses. The histological features of normal equine soft palate muscles have not been previously described. To describe the histological and morphometric features of normal equine soft palate muscles. The palatinus, palatopharyngeus, levator veli palatini and tensor veli palatini muscles of 6 Thoroughbred type horses were examined histologically and histochemically to assess their general morphology, fibre-type distribution and mean fibre diameter. The muscles of all 6 specimens showed very similar characteristics, including a low proportion of type 1 muscle fibres in the 4 different muscles examined, with the 3 muscles innervated by the pharyngeal branch of the vagus (i.e. palatopharyngeus, palatinus and levator veli palatini) having significantly fewer (P<0.005) type 1 muscle fibres compared to the tensor veli palatini. The mean fibre diameters were significantly (P<0.05) smaller in type 1 than type 2 fibres in all muscles except the palatinus. Considerable variability in mean fibre size diameter was evident in all muscles examined, with type 1 fibres in the levator veli palatini and rostral fasciculus of the palatopharyngeus and both fibre types in the caudal fasciculus of the palatopharyngeus having the most marked variation, with coefficients of variation >250 and the latter also having high levels of endomysial connective tissue. The palatinus had least variation in fibre size. Morphological characterisation of the normal soft palate muscles may provide reference values for future comparative studies with samples obtained from horses with palatal dysfunction. The palatinus appears to be the best muscle to histologically examine for evidence of muscle abnormality.


Extracellular signal-regulated kinase-1 and -2 respond differently to mitogenic and differentiative signaling pathways in myoblasts.
In this report we show that extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2) respond differently to signals that elicit proliferation and/or differentiation of myoblasts using the C2C12 cell line and nondifferentiating mutant NFB4 cells derived from them. Induction of differentiation by withdrawal of serum rendered ERKs in C2C12 myoblasts relatively insensitive to restimulation by serum. Instead, myogenic differentiation of C2C12 cells was associated with sustained activation of ERK-2 dependent on the insulin-like growth factor II (IGF-II) autocrine loop. By contrast, mutant NFB4 cells cultured under the same conditions remained proliferative and demonstrated robust activation of ERKs in response to serum. Similarly, a Gi-dependent signaling pathway induced activation of ERKs in NFB4 cells, but not in C2C12 cells, after stimulation by lysophosphatidic acid (LPA). In NFB4 cells partially rescued by prolonged IGF-I treatment, ERK activity remained responsive to Gi-dependent LPA stimulation, whereas rescue of NFB4 cells by constitutive expression of myogenin or MyoD, associated with activation of the IGF-II autocrine loop, rendered the Gi-signaling pathway refractory to LPA stimulation. Relatively high levels of G(alpha i2) were detected in NFB4 cells and IGF-I treated NFB4 cells, which correlated with responsive Gi signaling. Activation of the IGF-II autocrine loop in C2C12 and NFB4 myoblasts or treatment with IGF-II was associated with loss of G(alpha i2) and inhibition of Gi-dependent signaling. Thus, IGF-I and IGF-II activate distinct signaling cascades, with IGF-II eliciting a stronger differentiation effect correlated with down-regulation of G(alpha i2) protein. Short-term stimulation of NFB4 cells with IGF-I, a mitogenic signal for myoblasts, also induced ERK-1 and -2 activation. Transient stimulation of NFB4 cells with IGF-I while blocking activation of Gi-proteins is with pertussis toxin resulted in preferential activation of ERK-2 characteristic of differentiated C2C12 cells, suggesting that proliferation induced by IGF-I is Gi-dependent and separable from the IGF-I-signaling pathway that leads to differentiation.


Purification and properties of NAD(P)H: (quinone-acceptor) oxidoreductase of sugarbeet cells.
NAD(P)H:(quinone-acceptor) oxidoreductase [NAD(P)H-QR], a plant cytosolic protein, was purified from cultured sugarbeet cells by a combination of ammonium sulfate fractionation, FPLC Superdex 200 gel filtration, Q-Sepharose anion-exchange chromatography, and a final Blue Sepharose CL-6B affinity chromatography with an NADPH gradient. The subunit molecular mass is 24 kDa and the active protein (94 kDa) is a tetramer. The isoelectric point is 4.9. The enzyme was characterized by ping-pong kinetics and extremely elevated catalytic capacity. It prefers NADPH over NADH as electron donor (kcat/Km ratios of 1.7 x 10(8) M-1 S-1 and 8.3 x 10(7) M-1 S-1 for NADPH and NADH, respectively, with benzoquinone as electron acceptor). The acridone derivative 7-iodo-acridone-4-carboxylic acid is an efficient inhibitor (I0.5 = 5 x 10(-5) M), dicumarol is weakly inhibitory. The best acceptor substances are hydrophilic, short-chain quinones such as ubiquinone-0 (Q-0), benzoquinone and menadione, followed by duroquinone and ferricyanide, whereas hydrophobic quinones, cytochrome c and oxygen are reduced at negligible rates at best. Quinone acceptors are reduced by a two-electron reaction with no apparent release of free semiquinonic intermediates. This and the above properties suggest some relationship of NAD(P)H-QR to DT-diaphorase, an animal flavoprotein which, however, has distinct structural properties and is strongly inhibited by dicumarol. It is proposed that NAD(P)H-QR by scavenging unreduced quinones and making them prone to conjugation may act in plant tissues as a functional equivalent of DT-diaphorase.


Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen.
We describe studies of a human leukocyte antigen, termed Leu-13, that is defined by a mouse monoclonal antibody that reacts with T and B lymphocytes. Optimal staining of T cells requires a much higher concentration of alpha Leu-13 (greater than or equal to 200 micrograms/ml) than alpha Leu-4 (6 micrograms/ml). However, the fluorescence intensity of T cells labeled with alpha Leu-13, washed and kept at 4 degrees C for different periods, does not diminish more rapidly than the fluorescence of T cells stained with alpha Leu-4 and treated the same way. These results indicate that the novel binding pattern of alpha Leu-13 is not due to weak affinity. Immunoprecipitation and SDS-PAGE analysis indicates that alpha Leu-13 precipitates a major 16-kilodalton (16kd) band and a minor 26kd component from Nonidet P-40-solubilized membrane of normal T cells that are surface-labeled with 125I. The similar sizes of the 16kd to 26kd (Leu-13) and 22kd to 28kd (Leu-4) molecules prompted us to compare the capacity of alpha Leu-13 and alpha Leu-4 to trigger T cell functions, and to co-modulate and co-precipitate the T cell antigen receptor. Unlike alpha Leu-4, alpha Leu-13 does not trigger T cell proliferation or augment NK activity, but inhibits the mitogenic effect of alpha Leu-4/T3 antibodies. alpha Leu-13 also induces T cells to clump into large aggregates after 16 hr of culture at 37 degrees C, but not at 4 degrees C. T cell aggregation is triggered by concentrations of alpha Leu-13 as low as 12.5 ng/ml. At this concentration, alpha Leu-13 is not detectable on the surface of T cells by indirect immunofluorescence analysis in a FACS. On leukemic T cells, alpha Leu-4 was found to co-modulate and co-precipitate a 38kd to 44kd dimer having apparent idiotypic determinants, whereas alpha Leu-13 did not. The possible significance of these findings to immune regulation by T cells is discussed.


PRPH2 (Peripherin/RDS) mutations associated with different macular dystrophies in a Spanish population: a new mutation.
To assess the occurrence of PRPH2 mutations in patients presenting macular dystrophies and to describe their phenotype-genotype correlation. A total of 32 sporadic cases and 13 individuals from 5 families were studied. The patients presented early onset drusen, suspected pattern dystrophy (including adult-onset foveomacular vitelliform dystrophy [AOFVD]), or any presumed macular dystrophy producing neovascularization or atrophic changes documented before patients reached 50 years of age. In case of atrophy, this could be confined to the macula, which was considered to be central areolar choroidal dystrophy (CACD), or extend to the midperiphery of the retina, which we called diffuse macular dystrophy (DMD). Clinical workup and analysis of PRPH2, EFEMP1, and TIMP3 genes were done. Four mutations of the PRPH2 gene were found in 3 sporadic cases and 3 families (n = 11). A p.R46X mutation, previously described in CACD, was found in 3 members of a family with AOFVD and in a sporadic case with DMD. A p.L45F mutation, described before in retinitis pigmentosa, was found in a sporadic case of AOFVD. A p.R195L mutation previously described in CACD was found in 2 members of a family with CACD. The latter was found in a family and a sporadic case (from the same village as the family) and all of them presented DMD. A new p.V2091 mutation was found in a patient with AOFVD. New phenotypes were found for known mutations. No phenotype variation was observed in the members of the 3 families. A new mutation in PRPH2 gene was found.


Selection bias in pharmacy-based patient surveys.
To evaluate if there is a selection bias in drug utilization surveys on prescription drugs regularly conducted in Swedish pharmacies, to describe the direction of this potential bias and discuss the implications for the results. Age and gender distributions within patient survey samples from drug utilization surveys conducted during 2006-2010 are compared to the age and gender distribution of all Swedish patients, receiving the same drug or drugs, as given by the Swedish Prescribed Drug Register. The differences between the proportions of patients within the age and gender segments of each pair of survey/register data were calculated. In 25 (81%) out of 31 included surveys, patients aged 75 years or older are significantly underrepresented, as they are less likely to visit the pharmacy to collect their prescription drugs themselves and thus disqualify for the interviews. Data on women show similar results as overall survey data, whereas the underrepresentation of the oldest age group among men appears in a lower proportion of the surveys, 67%. The general consequence is a selection towards a healthier survey sample, but the consequences in the individual surveys vary, depending on what drug is being studied. Pharmacy-based patient surveys provide a convenient data collection method for patient self-reported data, but patients aged 75 years or older are consistently underrepresented. In surveys where this may influence the main research question, data should also be collected with other methods reaching the oldest patients.


Irritable bowel syndrome in psychiatric perspectives: a comprehensive review.
We comprehensively reviewed the irritable bowel syndrome (IBS) in terms of pathogenesis, psychiatric implications, general management and appropriate role of antidepressants, in particular selective serotonin uptake inhibitors (SSRIs) in the treatment of IBS. English language papers cited in MEDLINE and PychInfo from January 2000 to July 2006 were searched with a combination of the following key words: irritable bowel syndrome, 5-HT, pathogenesis, comorbid, psychiatry, treatment, psychotropic drugs, antidepressant, selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and sertraline), tricyclic antidepressants, review, meta-analysis and placebo. The papers on IBS describing the clinical features, pathophysiology, evaluation, management, and clinical trials [randomised placebo-controlled trial (RCT), open-label study or case report] were selected for this review. Further literatures were also detected from references of the identified papers. The epidemiology, diagnostic criteria, pathophysiology, general management, bidirectional comorbidity, summary of currently available RCTs and open-label studies investigating antidepressant efficacy (focusing on SSRIs), and suggestions for SSRI use in IBS were relevantly synthesised based on through review of identified data. This article summarised an up-to-date clinical overview of IBS in psychiatric perspectives as well as to position a current role of SSRIs in the treatment of IBS. From this review, the routine use of SSRIs for IBS treatment cannot be conclusive due to a paucity of RCTs, although a handful of RCTs suggested a potentially beneficial effect of SSRIs over placebo.


REMS pharmacy tasks: The adoption of an innovative electronic support system.
The objective of this study was to evaluate the pharmacy adoption rates of an online Risk Evaluation and Mitigation Strategy (REMS) Pharmacy Portal designed as an alternative for REMS-certified pharmacies to perform mandatory pharmacy dispense confirmations and to assess whether Pharmacy Portal uptake was affected by the pharmacy daily dispense volume. REMS-certified pharmacies dispensing lenalidomide (Revlimid), pomalidomide (Pomalyst), or thalidomide (Thalomid). Primarily specialty and hospital pharmacies in the limited distribution network that used the REMS Pharmacy Portal. A self-service pharmacy portal was developed to allow REMS-certified pharmacies to obtain confirmation numbers instead of calling a Celgene Customer Care Representative (CCR) or using the Interactive Voice Response System (IVR) system. The numbers of pharmacy dispense confirmations obtained were identified, and the mean percentages by quarter (Q) were calculated from January 2013 through August 2016 for the Pharmacy Portal, Celgene CCR, and IVR. In Q1 2013, the CCR and IVR options were used for 57% and 43% of dispense confirmations, respectively. After the training period, the Pharmacy Portal rapidly became the most used option (67% of confirmations from Q2 2014). By August 2016, data displayed the continued preference for the pharmacy portal (98% of all confirmations) regardless of the daily dispense volume of the pharmacy. As of March 30, 2018, the pharmacy portal continued to be the preferred option for all pharmacies (maintained at 98.5% use). There is an overwhelming REMS pharmacy preference to use the pharmacy portal over the IVR and CCR options, irrespective of the pharmacy daily dispense volume. The rapid uptake of the pharmacy portal is most likely attributed to robust and comprehensive 1-on-1 training and support provided by the REMS sponsor to the REMS-certified pharmacies, but also because it might be easier to use than the other options, resulting in reduced REMS burden for the pharmacy.


A novel technique for laminoplasty augmentation of spinal canal area using titanium miniplate stabilization. A computerized morphometric analysis.
Titanium miniplates are used to secure the posterior elements in the open position after expansive open-door laminoplasty. Preoperative and postoperative spinal canal dimensions are measured to assess the effectiveness of this technique. To develop a simple yet effective technique to stabilize the posterior elements after laminoplasty and to compare preoperative and postoperative spinal canal dimensions to accepted normal values. Expansive open-door laminoplasty has been offered as a simple alternative to laminectomy, which has been associated with postoperative kyphosis. Although the technique of laminoplasty is effective, a simple and reliable method of holding the posterior elements open has not been described. Ten myelopathic patients with multilevel cervical canal stenosis secondary to spondylosis or ossification of the posterior longitudinal ligament were treated with an expansive open-door laminoplasty. The posterior elements were stabilized in the open position with titanium miniplates. Computer-assisted morphometric analysis was performed on preoperative and postoperative computed tomography scans to obtain spinal canal dimensions. Plain radiographs were used to monitor construct integrity. The preoperative sagittal canal diameter was 8.2 +/- 0.96 mm, and the canal area was 180.6 +/- 33.7 mm2. These dimensions increased after surgery to 16.6 +/- 1.5 mm and 321.9 +/- 29.7 mm2, respectively. The titanium miniplate constructs did not fail during the follow-up period (mean, 26.4 months), and the decompression was maintained. The single significant complication was transient C5 radiculopathy. Normal canal dimensions can be reestablished with open-door laminoplasty. Achieving and maintaining an increased sagittal canal diameter is probably the most important change in anatomic parameters to facilitate neurologic recovery. The use of titanium miniplates to stabilize the posterior elements after laminoplasty is a simple, durable, and effective technique to maintain the increased sagittal diameter of the spinal canal.


Serum Carcinoembryonic Antigen Levels Before the First Curative Hepatectomy for Metastatic Colorectal Cancer Is a Predictor of Recurrence.
The aim of this study was to evaluate the usefulness of serum carcinoembryonic antigen (CEA) levels before the first curative hepatectomy for metastatic colorectal cancer as a predictor of recurrence. Between 2003 and 2010, 66 patients (45 male and 21 female) who underwent a first curative hepatectomy for metastatic colorectal cancer in our hospital were evaluated retrospectively. The mean patient age was 65.2 years (range=31-80 years). A total of 28 patients had synchronous liver metastasis, and the other 38 patients developed metachronous liver metastasis. The 5-year relapse-free survival rate after the first hepatectomy of the 16 patients with normal serum CEA level was 61.1%, whereas that of the 50 patients with abnormal serum CEA level was 34.3% (p<0.001). Among patients whose serum CEA levels were abnormal, the 5-year relapse-free survival rate after the first hepatectomy of the 34 patients with serum CEA levels less than 50 ng/ml was 48.1%, whereas that of the 16 patients with serum CEA level equal to or greater than 50 ng/ml was 6.3% (p<0.001). All eleven patients whose serum CEA levels were at least 100 ng/ml developed recurrence within one year after hepatectomy. Serum CEA levels before the first curative hepatectomy for metastatic colorectal cancer seem to be a predictor of recurrence.


Silicon-based wavelength division multiplexer using asymmetric grating-assisted couplers.
A wavelength division multiplexer (WDM) based on asymmetric grating-assisted couplers is proposed, which can flexibly adjust the bandwidth by changing the corrugation width of the grating. The simulation results show that, compared with asymmetric uniform grating-assisted couplers, asymmetric unilateral amplitude apodization grating-assisted couplers and asymmetric bilateral amplitude apodization grating-assisted couplers can effectively suppress the sidelobes. The experimental results show that the insertion loss of each wavelength channel is between 0.23dB and 0.58dB, and the sidelobe suppress ratio of both unilateral amplitude apodization grating-assisted couplers and bilateral amplitude apodization grating-assisted couplers is larger than 10dB, which reduces channel crosstalk and proves the feasibility of the wavelength division multiplexers.


H/D isotopic exchange in water interactions with the ferroelectric copolymer: Poly(vinylidene fluoride-trifluoroethylene) (70%:30%).
For both water and heavy water adsorption and absorption on crystalline poly(vinylidene fluoride with trifluoroethylene (30%)), P(VDF-TrFE 70:30), two distinctly different adsorption sites have been identified by thermal desorption spectroscopy. One adsorbed water species resembles ice and there is also an absorbed water species that interacts more strongly with the polymer thin film, and in addition, there is a polymer surface (polymer to ice interface) water species. We find that there is H/D exchange between the water or heavy water molecules and the ferroelectric polymer (largely -(CH2-CF2)-), particularly at the polymer surface.


Crystal structure analysis and in silico pKa calculations suggest strong pKa shifts of ligands as driving force for high-affinity binding to TGT.
A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNA(Asn,Asp,His,Tyr) against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested. One aim of previous studies was to address a hydrophobic pocket with different side chains attached to the parent skeletons. Disappointingly, no significant increase in binding affinity could be observed that could be explained by the disruption of a conserved water cluster. The ligand series examined in this study are based on the known scaffold lin-benzoguanine. Different side chains were introduced leading to 2-amino-lin-benzoguanines, which address a different pocket of the protein and avoid disruption of the water cluster. With the introduction of an amino group in the 2-position, a dramatic increase in binding affinity can be experienced. To explain this significant gain in binding affinity, Poisson-Boltzmann calculations were performed to explore pK(a) changes of ligand functional groups upon protein binding, they can differ significantly on going from aqueous solution to protein environment. For all complexes, a permanent protonation of the newly designed ligands is suggested, leading to a charge-assisted hydrogen bond in the protein-ligand complex. This increased strength in hydrogen bonding takes beneficial effect on binding affinity of the ligands, resulting in low-nanomolar binders. Crystal structures and docking emphasize the importance of the newly created charge-assisted hydrogen bond. A detailed analysis of the crystal structures in complex with substituted 2-amino-lin-benzoguanines indicate pronounced disorder of the attached side chains addressing the ribose 33 binding pocket. Docking suggests multiple orientations of these side chains. Obviously, an entropic advantage of the residual mobility experienced by these ligands in the bound state is beneficial and reveals an overall improved protein binding.


Eagle's syndrome: lesser cornu amputation: an alternative surgical solution?
A case is reported of a 42-year-old female patient, who presented with clinical symptoms of Eagle's syndrome, radiographic evidence of marginally elongated styloid processes as well as markedly elongated lesser cornua of the hyoid. The symptoms were successfully treated by amputating the lesser cornua of the hyoid. The patient has now been asymptomatic for more than 6 years.


Lumbar zygapophyseal joint injections in patients with chronic lower back pain.
This study was designed to assess the diagnostic value and clinical benefits of lumbar zygapophyseal joint injections in patients with chronic lower back pain. Two hundred and seventy-seven patients (136 males and 141 females, aged 15-82 years) with chronic lower back pain were enrolled in the trial and met the following criteria: pain for more than 1 year; no root signs; and no history of back surgery. Under fluoroscope, a 0.8-1.5 mL mixture of lidocaine, betamethasone dipropionate and iopamidol (1:1:0.5) was injected into each joint after intra-articular localization of the needle tip was confirmed. A questionnaire with a pain scale was administered immediately or the day after injection, and then after 1, 3, 6 and 12 weeks. Partial arthrograms were reviewed by a radiologist. Four hundred and forty-nine joint injections were performed in 277 patients (L3-4, n = 76; L4-5, n = 272; L5-S1, n = 101). Bilateral injections were performed in 117 patients (42.2%). The study group comprised 204 patients (73.6%) with an excellent or good response, whereas the control group comprised the remaining 73 patients (26.4%). The rates of good response in the study group were 72.1% (147/204) after 3 weeks, 40.7% (83/204) after 6 weeks, and 31.4% (64/204) after 12 weeks. Partial arthrograms revealed 25 patients (9.0%) with synovial cysts (L3-4, n = 3; L4-5, n = 14; L5-S1, n = 8); 23 of these patients (92.0%) had a good response to the injections. Five of the 6 patients with spondylolysis (83.3%), having abnormal communication between the injected and contiguous joint, had a good response to the injections. The abovementioned, abnormal partial-arthrogram findings correlated significantly with the rate of good response to the injections. Although 3 patients had contrast medium extravasated into the epidural space during injection, none of the 277 patients had deteriorating lower back pain after the injections. Lumbar zygapophyseal joint injections, as a useful diagnostic tool for facet joint syndrome, could also have useful palliative effects in the management of chronic lower back pain.


Reactivity of Metal Clusters.
We summarize here the research advances on the reactivity of metal clusters. After a simple introduction of apparatuses used for gas-phase cluster reactions, we focus on the reactivity of metal clusters with various polar and nonpolar molecules in the gas phase and illustrate how elementary reactions of metal clusters proceed one-step at a time under a combination of geometric and electronic reorganization. The topics discussed in this study include chemical adsorption, addition reaction, cleavage of chemical bonds, etching effect, spin effect, the harpoon mechanism, and the complementary active sites (CAS) mechanism, among others. Insights into the reactivity of metal clusters not only facilitate a better understanding of the fundamentals in condensed-phase chemistry but also provide a way to dissect the stability and reactivity of monolayer-protected clusters synthesized via wet chemistry.


Comparative study on the vitamin C contents of the food legume seeds.
We found that dehydrated legume seeds (6 genera, 19 species and cultivated varieties) contained considerable amounts of vitamin C (VC). The average value of total VC content per 100 g of dry weight in dehydrated seeds varied from 0.24 mg (kidney beans) to 4.14 mg (green peas). Yard beans showed highest values among all legumes examined here in the both dehydrated and rehydrated forms (3.19 and 10.8 mg, respectively). By soaking for 16 h in the dark at 20(o)C, total VC contents of black grams and mung beans increased to 3.1- and 4.5-fold, respectively. However, three varieties of green peas (Hakuryu, Kurumeyutaka, and Nankaimidori) significantly lost their VC during the same soaking treatment. Total VC content of a rehydrated and cooked mung beans was higher than that of a dehydrated form. Appreciable amounts of total VC were detected in the immature seeds of six different genera such as yard beans, kidney beans, broad beans, green peas, soybeans and peanuts. Except for mung beans, 70-100% of VC in dehydrated seeds of adzuki beans, broad beans, green peas, black soybeans, and soybeans was lost by boiling. Total VC and L-ascorbic acid in mung beans, green peas, broad beans, black soybeans, and adzuki beans remained even after boiling, suggesting that it is possible to obtain VC from the cooked forms of these legume seeds.


HPLC and light scattering detection allow the determination of phospholipids in biological samples and the assay of phospholipase A2.
Some applications to biological samples of a method for the separation and the quantitative analysis of phospholipids by high performance liquid chromatography (HPLC) and light scattering mass detection are described. Results obtained in the determination of phospholipid classes from rat tissues such as liver, heart and kidney have been compared with data from the literature. The method has been applied to the evaluation of phospholipids in human low-density lipoproteins (LDL), about which little is known. The procedure is also suitable for a rapid and reliable assay of the water-soluble phospholipase A2 activity; the relationship between the aggregation state of substrate phospholipids (mixed micelles, multilamellar and unilamellar vesicles) and the enzyme activity has been studied.


The complete larval development of Pagurus maculosus Komai & Imafuku, 1996 (Decapoda, Anomura, Paguridae) reared in the laboratory, and a comparison with sympatric species.
The complete larval development of the hermit crab Pagurus maculosus, is described and illustrated based on specimens reared in the laboratory at 15 °C and 33-35 PSU. Newly hatched larvae invariably passed through a short prezoeal stage (10 minutes to 2 hours), four zoeal stages (each of 7 days,) and one megalopal stage (14 days). Distinct morphological features of each larval stage of the present study are compared with other closely related species in Japanese waters, and we found many differences in morphology and the duration of zoeal stages between them. We mentioned significant diagnostic characters separating this species from other congeners in Japanese waters that include the presence of red-yellowish chromatophores on the maxillipeds. This is the first report of complete larvae development of Pagurus maculosus.


Partial agonists and G protein-coupled receptor desensitization.
Weak or partial agonists induce less desensitization of G protein-coupled receptors (GPCRs) than do strong agonists. However, there have been few attempts to relate partial agonism quantitatively with the various parameters of agonist-induced desensitization, and to elucidate the mechanisms involved. Our understanding of how the treatment of cells and tissues with partial agonists affects their capacity to activate receptors is based on continued progress in defining partial agonism and the mechanisms of desensitization in which protein kinases, phosphatases, endocytosis and recycling play various roles. In this review, current research concerning partial-agonist-induced desensitization of GPCRs and the nature of partial agonism is summarized, and an attempt is made to put the existing knowledge into a working hypothesis concerning the mechanisms that account for the reduced desensitization in response to partial agonists.


[Genital bowenoid papulosis. Pseudo-Bowen's disease of the genital area].
This report deals with a new disease, which is characterized by multiple reddish papules on the genitalia of young adults. The histological picture shows changes of squamous cell carcinoma in situ. The possible etiology is discussed. It is too early to predict the biological behaviour of these lesions.


Praziquantel: a new schistosomicide against Schistosoma mansoni.
2-Cyclo-hexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide), a new schistosomicide, given to subjects with Schistosoma mansoni infections in a single oral dose of 40 mg/kg or 50 mg/kg in 2 divided doses resulted in probable cure rates at 6 months of 74% and 88.1%, respectively. The corresponding reduction in egg excretion of the non-cured cases was 96.9% and 97.3%. Side effects were not severe but included urticaria, loose bowel motions, abdominal pain and sleepiness.


[Development and evaluation of an ADHD teacher group training--a pilot study].
In the introduction is shown that no controlled studies of teacher training programs in children with Attention Deficit Hyperactivity Disorder (ADHD) have been published in German research literature as yet in spite of high demand for educational inservice training. The aim of the present study is the development and evaluation of a two-step ADHD teacher group training. In step 1 a group training (12 h) was performed with 18 advisory teachers. The curriculum included ADHD theory, contingency management and "antecedent" TEACCH-oriented school-based interventions (Schopler 1997; Bregman and Gerdtz 1997). In step 2 then a subsample of 6 advisory teachers supervised 10 classroom teachers of 11 primary school students (mean age 8.6 yrs.) with ADHD symptoms, who were assigned to two experimental groups. The classroom teachers of the Standard Treatment Group (n=5 students) received the basic module "ADHD theory and school-based interventions" (6 h), the teachers of the Intensive Treatment Group (n=6 students) received the same basic module plus the module "Student-related training in Contingency Management" (in total 14h). The group training process was evaluated by teacher satisfaction ratings and knowledge test. The training effect on student behavior was evaluated by teacher ratings within a two-group-pre-post-follow-up design. The main results are: (a) The group training process was mostly evaluated favorably; knowledge increased significantly; (b) ADHD symptoms were reduced significantly in both treatment groups, with stronger and sustained improvement of problem behaviors and adaptive functioning in the Intensive Treatment Group. These findings provide some consistent evidence, that classroom behaviors of children with ADHD symptoms can be improved substantially by a teacher mediator training approach.


Fibrin clot retraction by human skin fibroblasts: effects of ADP and thrombin.
Thrombin stimulated human skin fibroblasts to retract fibrin clots. When Bothrops marajoensis thrombinlike enzyme was substituted for thrombin, no retraction occurred. Fibroblasts were found to contain 12 nmole of ATP and 3.6 nmole of ADP/mg of protein, a value closely resembling that of nonmetabolic adenine nucleotides in platelets. Thrombin caused neither release of adenine nucleotides from the suspension of fibroblasts harvested enzymatically nor did addition of ADP stimulate fibroblasts to retract fibrin clots.


Two step reconstruction of traumatic ear skin avulsion using Integra graft.
Treatment of traumatic ear injuries have always been a challenge. Preservation of the auricular cartilage is key for reconstruction. Many techniques have been reported for the management of exposed ear perichondrium. We present patient who sustained right ear soft tissue avulsion. Initial examination the patient revealed skin avulsion with exposed cartilage from the concha, scapha and antihelix on the right ear. The treatment sequence included debridement and application of Integra graft. This was followed by dressing changes every three days and three weeks. Once adequate vascularization was noted a split thickness skin graft was used for final reconstruction. Integra has been widely used for the management of burns as well as exposed bone and cartilage. However, its use in traumatic ear injuries has not been reported. This technique allowed for the reconstruction of a large skin avulsion from the right ear with minimal donor site morbidity and avoidance of local rotational flaps that could hinder later reconstructions if needed.


Oral contraceptives and thrombotic diseases: impact of new epidemiological studies.
Oral contraceptives (OCs) are, or perhaps more correctly, were, until recently, being taken by approximately 65 million women worldwide, which corresponds to approximately 6% of all women of reproductive age. OCs have been available since the early 1960s, and there is substantial evidence to suggest that no single medication has had such a profound impact on our reproductive and social life than the pill. In the Scandinavian countries, 30-50% of young women have been reported to be using OCs. Its widespread use throughout the world for several decades indicates that women and their doctors have considered that the benefits of OCs outweigh potential side effects. On October 18, 1995, the Committee on Safety of Medicines in the United Kingdom sent a warning to all British doctors and pharmacists about OCs containing desogestrel or gestodene. A similar warning was subsequently distributed by the German and Norwegian health authorities. As these OC types dominate the market in Northern Europe, many gynaecologists, general practitioners, women of reproductive age, different national bodies on drug safety, and people in general have been asking: * What was the background for these actions? * How do we interpret the new studies? * What do we do now concerning prescription of OCs? * What is the moral of this story?


Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage.
Cell survival after genotoxic stress is determined by a counterbalance of pro- and anti-death factors. Sirtuins (SIRTs) are deacetylases that promote cell survival whereas poly(ADP-ribose) polymerases (PARPs) can act both as survival and death inducing factor and the two protein families are strictly dependent on NAD(+) for their activities. Here we report that SIRT1 modulates PARP-1 activity upon DNA damage. Activation of SIRT1 by resveratrol leads to reduced PARP-1 activity and there is a drastic increase in PAR synthesis in sirt1-null cells. The unbalanced regulation of PARP-1 in the absence of SIRT1 results in AIF (apoptosis inducing factor)-mediated cell death. Our findings establish a functional link between the two NAD+-dependent enzyme systems and provide a physiological interpretation for the mechanism of death in cells lacking SIRT1.


Gustatory responses of cortical neurons in rats. III. Neural and behavioral measures compared.
The responses of 39 cortical neurons to 13 kinds of taste stimuli including the four putative basic taste solutions (sucrose, NaCl, HCl, and quinine HCl) applied to the anterior portion of the tongue were recorded extracellularly in lightly anesthetized rats. The neural responses were analyzed in terms of the four hypotheses of quality coding: across-neuron response pattern, labeled-line, matrix pattern, and across-region response pattern notions. Animals were given a conditioned taste aversion to one of the 11 stimuli by pairing it with a gastrointestinal illness caused by intraperitoneal injection of 0.15 M LiCl. Behavioral taste profiles were constructed for each stimulus from the suppression of rate of drinking, which indicates the extent of generalization of aversion to each of the four basic taste stimuli. Neural taste profiles of each taste stimulus, which indicate the relation of the taste of a stimulus to each taste of the four basic stimuli, differed more or less depending on the kind of quality-coding notions employed. Among the four analyses, across-region correlation coefficients that were derived from an across-region response-pattern theory showed the highest correlation with the behavioral suppression rates. Therefore we conclude that processing of taste information in the cortex involves differences in both response magnitude across neurons and the spatial localization of those neurons. Fluid intake per day of each of the 12 taste solutions was measured by the single-bottle preference method. When the amount of intake was described in terms of an hedonic index (HI), which indicates the hedonic aspect of the taste of each solution, HI's for sucrose, NaCl, HCl, and quinine were 1.17, 0.43, -0.49, and -0.89, respectively. These values represent the degree of deviation of solution intake above (i.e., preferable) or below (aversive) the standard water intake. Then, HI's were calculated for each of the 12 taste stimuli based on the neural taste profiles and actual HI's for each of the four basic taste stimuli. The correlations between the calculated and the actual (or behaviorally obtained) HI's were very high (ranging from 0.832 to 0.941). This result suggests that the hedonic dimension of taste can be matched well by any one of the four proposed hypotheses.


Large-cell lymphoma presenting with hepatic sinusoidal infiltration.
We describe a case of large-cell lymphoma of B-cell phenotype with clinicopathologic features resembling malignant histiocytosis. The clinical presentation was characterized by fever, anemia, thrombocytopenia, coagulopathy, and elevated liver enzyme levels. These features and the finding of a predominantly sinusoidal infiltrate of neoplastic cells on liver biopsy raised the suspicion of malignant histiocytosis. The patient subsequently developed supraclavicular lymphadenopathy, which proved to be due to a diffuse large-cell lymphoma. Immunophenotypic studies performed on the lymph node and the original liver biopsy specimen established the B-cell nature of neoplastic cells at both sites. This case highlights a rare pattern of hepatic involvement by large-cell lymphoma, and contrasts the latter with other hematologic disorders associated with hepatic sinusoidal infiltrates.


Developmental abnormalities of NT mouse embryos appear early after implantation.
In mammals, cloning by nuclear transfer (NT) into an enucleated oocyte is a very inefficient process, even if it can generate healthy adults. We show that blastocysts derived from embryonic stem (ES) donor cells develop at a high rate, correctly express the pluripotential marker gene Oct4 in ICM cells and display normal growth in vitro. Moreover, the majority of them implant in the uterus of recipient females. We combine embryological studies, gene expression analysis during gastrulation and generation of chimaeric embryos to identify the developmental origin (stage and tissue affected) of NT embryo mortality. The majority died before mid-gestation from defects arising early, either at peri-implantation stages or during the gastrulation period. The first type of defect is a non-cell autonomous defect of the epiblast cells and is rescued by complementation of NT blastocysts with normal ES or ICM cells. The second type of defect affects growth regulation and the shape of the embryo but does not directly impair the initial establishment of the patterning of the embryo. Only chimaeras formed by the aggregation of NT and tetraploid embryos reveal no growth abnormalities at gastrulation. These studies indicate that the trophoblast cell lineage is the primary source of these defects. These embryological studies provide a solid basis for understanding reprogramming errors in NT embryos. In addition, they unveil new aspects of growth regulation while increasing our knowledge on the role of crosstalk between the extra-embryonic and the embryonic regions of the conceptus in the control of growth and morphogenesis.


Re-irradiation with interstitial pulsed-dose-rate brachytherapy for unresectable recurrent head and neck carcinoma.
To assess the long-term results of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy combined with simultaneous chemotherapy in selected patients with recurrent head and neck tumors not amenable to salvage surgery. A total of 51 patients with recurrent head and neck cancer were treated with interstitial PDR brachytherapy. Forty patients (78%) had salvage brachytherapy alone using a median total dose of 60 Gy. Salvage brachytherapy in combination with external beam therapy was performed in 11 patients (22%) using a median total dose of DREF=27 Gy. Simultaneously with the PDR brachytherapy, a concomitant chemotherapy was administered in 35/51 (69%) of patients. The analysis was performed after a median followup of 58 months. Local control rates calculated according to Kaplan-Meier after 2 and 5 years were 71% and 57%, respectively. Comparing results of salvage PDR brachytherapy with or without simultaneous chemotherapy, the 5-year local recurrence-free survival rates were 78.9% vs. 38.5% (p=0.01), respectively. No other patient or treatment-related parameters had a significant influence on treatment results. A total of 9/51 (17.7%) and 6/51 (11.8%) patients developed soft-tissue necrosis or bone necrosis, respectively, but only 2% of patients required surgical treatment. PDR interstitial brachytherapy with pulse doses between 0.4 and 0.7 Gy/h/24 h with simultaneous chemotherapy is an effective and safe option for curative therapy in selected patients with head and neck cancer in previously irradiated areas, which are not suitable for salvage surgery.


Sinusoidal heating method to noninvasively measure tissue perfusion.
Noninvasively measuring the tissue blood perfusion has been an important however difficult problem in the biomedical engineering field. Based on the newly developed phase-shift principle, an improved sinusoidal heating method to estimate the perfusion was proposed in this paper to replace the original heating algorithm. The phase shift between the sinusoidal heat flux and the surface temperature response was both theoretically and experimentally revealed to be a time-dependent value which however will approach a constant value after a sufficiently long time. Only using this constant phase shift can the perfusion be properly estimated. Following the theory, an instrument consisting of low-frequency sinusoidal signal generator, power amplifier, heating plate, temperature and heat flux monitoring unit, as well as the data-acquisition system was carefully constructed. It allows generating a high-quality sinusoidal heat flux whose frequency and magnitude can be easily regulated. An auxiliary heat-conducting plate was introduced to simultaneously measure the surface temperature and the heat flux, which are hard to do otherwise. Experiments on human bodies were performed and the forearm perfusion was estimated and then validated through a constant surface heating experiment. Several issues related to the instrument integration and perfusion measurement were discussed. The instrument was also tested through experiments on nonperfused materials and good results were obtained. These efforts will help to build a compact device for noninvasively measuring the human perfusion, which may have significant applications in future clinics.


Coherent dynamical recoupling of diffusion-driven decoherence in magnetic resonance.
During recent years, dynamical decoupling (DD) has gained relevance as a tool for manipulating and interrogating quantum systems. This is particularly relevant for spins involved in nuclear magnetic resonance (NMR), where DD sequences can be used to prolong quantum coherences, or to selectively couple or decouple the effects imposed by random environmental fluctuations. In this Letter, we show that these concepts can be exploited to selectively recouple diffusion processes in restricted spaces. The ensuing method provides a novel tool to measure restriction lengths in confined systems such as capillaries, pores or cells. The principles of this method for selectively recoupling diffusion-driven decoherence, its standing within the context of diffusion NMR, extensions to the characterization of other kinds of quantum fluctuations, and corroborating experiments, are presented.


Evaluation of Ayush-64 for blood schizontocidal activity against rodent and simian malaria parasites.
Ayush-64, a new herbal antimalarial drug developed by the Central Council for Ayurveda and Siddha, was evaluated for direct parasiticidal action against P. berghei and P. yoelii nigeriensis in swiss mice and P. cynomolgi B and P. knowlesi in rhesus monkeys. No blood schizontocidal activity could be demonstrated against any of the four malaria parasites.


Structure and function of the vertebrate magnetic sense.
Some vertebrates can navigate over long distances using the Earth's magnetic field, but the sensory system that they use to do so has remained a mystery. Here we describe the key components of a magnetic sense underpinning this navigational ability in a single species, the rainbow trout (Oncorhynchus mykiss). We report behavioural and electrophysiological responses to magnetic fields and identify an area in the nose of the trout where candidate magnetoreceptor cells are located. We have tracked the sensory pathway from these newly identified candidate magnetoreceptor cells to the brain and associated the system with a learned response to magnetic fields.


Quantification of whey proteins by reversed phase-HPLC and effectiveness of mid-infrared spectroscopy for their rapid prediction in sweet whey.
In the dairy industry, membrane filtration is used to reduce the amount of whey waste and, simultaneously, to recover whey proteins (WP). The composition of WP can strongly affect the filtration treatment of whey, and rapid determination of WP fractions would be of interest for dairy producers to monitor WP recovery. This study aimed to develop mid-infrared spectroscopy (MIRS) prediction models for the rapid quantification of protein in sweet whey, using a validated rapid reversed phase (RP)-HPLC as a reference method. Quantified WP included α-lactalbumin (α-LA), β-lactoglobulin (β-LG) A and B, bovine serum albumin, caseinomacropeptides, and proteose peptone. Validation of RP-HPLC was performed by calculating the relative standard deviation (RSD) in repeatability and reproducibility tests for WP retention time and peak areas. Samples of liquid whey (n=187) were analyzed by RP-HPLC and scanned through MIRS to collect spectral information (900 to 4,000 cm(-1)); statistical analysis was carried out through partial least squares regression and random cross-validation procedure. Retention times in RP-HPLC method were stable (RSD between 0.03 and 0.80%), whereas the RSD of peak area (from 0.25 to 8.48%) was affected by WP relative abundance. Higher coefficients of determination in validation for MIRS model were obtained for protein fractions present in whey in large amounts, such as β-LG (0.58), total identified WP (0.58), and α-LA (0.56). Results of this study suggest that MIRS is an easy method for rapid quantification of detail protein in sweet whey, even if better resolution was achieved with the method based on RP-HPLC. The prediction of WP in sweet whey by MIRS might be used for screening and for classifying sweet whey according to its total and individual WP contents.


[Graft-versus-host disease and xenotransplantation].
The pathogenesis, mechanism, manifestation and diagnosis of graft-versus-host disease(GVHD) are reviewed in this article. The relevant articles in recent public magazines were reviewed and summarized. It was indicated that GVHD occurred in the conditioned recipients in animal experiments and clinical transplantations. Humoral and cellular factors were involved in GVHD, which could be diagnosed and classified according to their characteristics. As a kind of interactions between the host and donor, GVHD are severely harmful to the host. It may also occur in xenotransplantation, where GVHD can be utilized in the studies on transplant immunology, oncology etc. Xenogeneic GVHD is receiving more and more attentions.