Evolutionary Fuzzy Block-Matching-Based Camera Raw Image Denoising.
An evolutionary fuzzy block-matching-based image denoising algorithm is proposed to remove noise from a camera raw image. Recently, a variance stabilization transform is widely used to stabilize the noise variance, so that a Gaussian denoising algorithm can be used to remove the signal-dependent noise in camera sensors. However, in the stabilized domain, the existed denoising algorithm may blur too much detail. To provide a better estimate of the noise-free signal, a new block-matching approach is proposed to find similar blocks by the use of a type-2 fuzzy logic system (FLS). Then, these similar blocks are averaged with the weightings which are determined by the FLS. Finally, an efficient differential evolution is used to further improve the performance of the proposed denoising algorithm. The experimental results show that the proposed denoising algorithm effectively improves the performance of image denoising. Furthermore, the average performance of the proposed method is better than those of two state-of-the-art image denoising algorithms in subjective and objective measures.


Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats.
Opiate withdrawal has been correlated with decreased extracellular dopamine (DA) levels in the nucleus accumbens (NAC) of morphine-dependent rats. The authors tested the hypothesis that DA transmission plays a critical role in the induction of motivational and somatic withdrawal symptoms. First, the authors used a 6-hydroxydopamine-induced lesion of the NAC to chronically disrupt mesolimbic DA transmission. Second, global DA neurotransmission was acutely stimulated by the nonselective DA agonist (apomorphine) or inhibited by nonselective DA antagonists (droperidol or flupentixol). Morphine-dependent rats bearing 6-hydroxydopamine-induced lesions displayed naloxone-precipitated motivational and somatic withdrawal symptoms similar to those of sham-lesioned rats. Administration of apomorphine did not reduce naloxone-induced opiate withdrawal. Moreover, in total absence of naloxone, DA antagonists did not precipitate either conditioned place aversion or somatic abstinence signs in dependent rats. Taken together, these findings suggested that DA transmission is not critical for the induction of opiate withdrawal syndrome.


Effective local control of malignant melanoma by intratumoural injection of a beta-emitting radionuclide.
Intratumoural injection of an unsealed beta-emitting radionuclide is a new technique for the local control of tumours that has the advantage of delivering a higher radiation dose to tumour while minimising radiation hazard to the surrounding normal tissues. In this study, therapeutic effect, morphological alterations and biological responses to the high-dose continuous irradiation delivered using this new technique were evaluated in an animal model with B16 melanoma. For evaluation of the therapeutic effect, 92 C57BL/6 mice with B16 melanoma were divided into four groups. In each group, intratumoural injections were performed when the tumour measured approximately 1 cm along its long axis. Group 1 (n=25) received 0.3 ml of normal saline, group 2 (n=15) 37 MBq of carrier-free holmium-166 in 0.3 ml saline, group 3 (n=27) 185 MBq of 166Ho in 0.3 ml saline and group 4 (n=25) 185 MBq of 166Ho in 0.5 ml saline. In addition, another 30 mice were used for morphological and biological analysis of the radiation effect. These 30 mice were injected with 185 MBq of 166Ho in 0.3 ml saline, and five were sacrificed at each of the following six time points: before injection and 1, 2, 3, 6 and 14 days post injection. Haematoxylin-eosin (H&E) staining, immunohistochemical analysis for p53, p21, PCNA and cyclin D1, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) staining, reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry were performed. For visual side-by-side comparison, melanoma cells were inoculated bilaterally into the back of ten additional mice, and 185 MBq of 166Ho in 0.3 ml of saline or an equal volume of normal saline was injected separately into the bilateral tumours. Nine days after inoculation of melanoma cells, mean tumour volume reached 492.5-631.9 mm3. Tumours of the control group (group 1) showed rapid growth, and the mean tumour volume reached approximately 30 times the original volume. None of the control group lived for more than 16 days following the injection of normal saline. On the other hand, mean tumour volume of the treated groups showed a gradual decrease, and 67%-74% of the treated animals were alive when all the control animals had died. The median survival of the control group was 9 days following injection, whereas it was 29 days in group 2, 33 days in group 3 and 33 days in group 4. The survival rate of group 3 was higher than that of groups 2 and 4, but statistical significance was not observed. H&E stain of the tumours demonstrated central necrosis and peripheral residual cells with progressive cytoplasmic and nuclear swelling without apoptotic features. Expression of proteins and mRNAs of p53 and bax increased until 3 days, as compared with 48 h for p21; thereafter, the expression gradually decreased. TUNEL-positive nuclei could be seen from 2 days until 2 weeks after treatment. Flow cytometry did not demonstrate an increase in apoptotic features as compared with the control animals. In conclusion, intratumoural injection of the unsealed beta-emitting radionuclide 166Ho appears to be a promising alternative radiotherapeutic modality for the local control of malignant melanoma. The main cell death mechanisms with this technique seem to be radiation-induced central necrosis and peripheral growth arrest or secondary necrosis of tumour cells, rather than apoptosis.


Psychiatrist says counselling via e-mail may be yet another medical use for Internet.
The head of the Personality Disorders Clinic at the University of Michigan recently told the annual meeting of the American Psychiatric Association that he has used "e-mail counselling" to treat seriously ill patients. He provided some advice about the possible use of e-mail to supplement face-to-face sessions in the psychiatrist's office.


Observation of flow variation in capillaries of artificial blood vessel by producing microbubble aggregations.
Microbubbles form their aggregations between the neighboring microbubbles by the effect of secondary Bjerknes force under ultrasound exposure. However, because of the difficulty to reproduce a capillary-mimicking artificial blood vessel, the behavior of aggregations in a capillary has not been predicted. Thus we prepared artificial blood vessels including a capillary model, which was made of poly(vinyl alcohol) (PVA) by grayscale lithography method, with minimum diameter of the path of 0.5 mm. By using this model we investigated the possibility of artificial embolization, where the microbubble aggregations might block entire vessels not to penetrate flow in downstream. Confirming that the sizes of flown aggregation were greater than the section area of the minimum path in the capillary model, we investigated the probability of path block in it. As the results we confirmed the probability increased in proportion to sound pressure and inversely to flow velocity. We are going to investigate with more kinds of parameters to enhance the possibility of artificial embolization.


Predicting EEG single trial responses with simultaneous fMRI and relevance vector machine regression.
The combination of electroencephalography (EEG) and functional Magnetic Resonance Imaging (fMRI) has been proposed as a tool to study brain dynamics with both high temporal and high spatial resolution. Integration through EEG-fMRI trial-by-trial coupling has been proposed as a method to combine the different data sets and achieve temporal expansion of the fMRI data (Eichele et al., 2005). To fully benefit of this type of analysis simultaneous EEG-fMRI acquisitions are necessary (Debener et al., 2006). Here we address the issue of predicting the signal in one modality using information from the other modality. We use multivariate Relevance Vector Machine (RVM) regression to "learn" the relation between fMRI activation patterns and simultaneously acquired EEG responses in the context of a complex cognitive task entailing an auditory cue, visual mental imagery and a control visual target. We show that multivariate regression is a valuable approach for predicting evoked and induced oscillatory EEG responses from fMRI time series. Prediction of EEG from fMRI is largely influenced by the overall filtering effects of the hemodynamic response function. However, a detailed analysis of the auditory evoked responses shows that there is a small but significant contribution of single trial modulations that can be exploited for linking spatially-distributed patterns of fMRI activation to specific components of the simultaneously-recorded EEG signal.


DNA vaccine encoding prostatic acid phosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostate cancer.
Prostatic acid phosphatase (PAP) is a tumor antigen in prostate cancer and the target of several anti-tumor vaccines in earlier clinical trials. Ultimately, the goal of anti-tumor vaccines is to elicit a sustainable immune response, able to eradicate a tumor, or at least restrain its growth. We have investigated plasmid DNA vaccines and have previously conducted a phase 1 trial in which patients with recurrent prostate cancer were vaccinated with a DNA vaccine encoding PAP. In this study, we investigated the immunologic efficacy of subsequent booster immunizations, and conducted more detailed longitudinal immune analysis, to answer several questions aimed at guiding optimal schedules of vaccine administration for future clinical trials. We report that antigen-specific cytolytic T-cell responses were amplified after immunization in 7 of 12 human leukocyte antigen-A2-expressing individuals, and that multiple immunizations seemed necessary to elicit PAP-specific interferon-gamma-secreting immune responses detectable by enzyme-linked immunosorbent spot assay. Moreover, among individuals who experienced a >/=200% increase in prostate-specific antigen doubling time, long-term PAP-specific interferon-gamma-secreting T-cell responses were detectable in 6 of 8, but in only 1 of 14 individuals without an observed change in prostate-specific antigen doubling time (P=0.001). Finally, we identified that immune responses elicited could be further amplified by subsequent booster immunizations. These results suggest that future trials using this DNA vaccine, and potentially other anti-tumor DNA vaccines, could investigate ongoing schedules of administration with periodic booster immunizations. Moreover, these results suggest that DNA vaccines targeting PAP could potentially be combined in heterologous immunization strategies with other vaccines to further augment PAP-specific T-cell immunity.


Medicinal mushroom Ganoderma lucidum as a potent elicitor in production of t-resveratrol and t-piceatannol in peanut calluses.
Phytoalexins t-resveratrol and t-piceatannol, the well-known health-promoting active components in plants, are secondary metabolites generated upon biotic or abiotic stresses. We have reported UV-irradiated peanut callus is a potent means to produce these compounds (J. Agric. Food Chem. 2005, 53, 3877). In this work, the effects of fungi and chemical elicitors on induction of t-resveratrol and t-piceatannol were examined. Results showed the investigated fungi Botryodiplodia theobromae and Reishi Ganoderma lucidum were generally more effective than chemical stress methyl jasmonate, salicylic acid, and sucrose. As high as 15.46+/-9.85 microg of t-resveratrol and 6.93+/-2.03 microg of t-piceatannol could be elicited in each gram of callus by sterilized G. lucidum mycelium (80 mg). Although much more sterilized G. ludicum mycelia was required to induce similar level of t-resveratrol and t-piceatannol in comparison to the sterilized B. theobromae mycelia (1 mg), uptake of the G. ludicum mycelium may provide a variety of health-promoting effects. Our findings suggest G. ludicum mycelium-treated peanut callus is a good source of bioactive components.


Shyness, sociability, and social dysfunction in schizophrenia.
Recent bio-developmental models of shyness traits (Schmidt, L.A., Fox, N.A., 1998. The development and outcomes of childhood shyness. Annals of Child Development 13, 1--20; Schmidt, L.A. Fox, N.A., 1999. Conceptual, biological, and behavioural distinctions among different types of shy children. In: Schmidt, L.A., Schulkin, J. (Eds.), Extreme Fear, Shyness, and Social Phobia: Origins, Biological Mechanisms, and Clinical Outcomes. Oxford University Press, New York, pp. 47--66) have proposed that childhood shyness and early sociability troubles may be a precursor to pervasive social dysfunction in adulthood. An important question in testing the vulnerability model is to determine the severity of shyness among adults who have a serious social dysfunction, such as individuals diagnosed with schizophrenia. The Cheek and Buss Shyness and Sociability Scales (Cheek, J.M., Buss, A.H., 1981. Shyness and sociability. Journal of Personality and Social Psychology 41, 330--339) and the Reznick Retrospective Self-report of Inhibition (Reznick, J.S., Hegeman, I.N., Kaufman, E.R., Woods, S.W., Jacobs, M., 1992. Retrospective and concurrent self-report of behavioural inhibition and their relation to adult mental health. Development and Psychopathology 4, 301--321) were administered to 23 schizophrenia outpatients and 23 control subjects matched for age and sex. The results indicated that individuals with schizophrenia showed significantly more shyness (P<0.004), lower sociability (P<0.02) and more recollections of childhood social troubles (P<0.007) compared with the control group. Within the schizophrenia group, both shyness traits (P<0.04) and limited sociability (P<0.01) were clearly associated with interpersonal dysfunction, while significant correlations were also found between troubled sociability and negative symptoms (P<0.05). The findings of shyness traits, impaired sociability and more recollections of childhood social difficulties among stable outpatients diagnosed with schizophrenia are consistent with predictions based on a bio-developmental shyness vulnerability model.


Comparing quality of mental health care for public-sector and privately insured populations.
This study examined the methodological difficulties of comparing quality of care in large health care systems. It demonstrated methods for measuring quality of mental health care and, using these measures, compared patients from Department of Veterans Affairs (VA) hospitals with privately insured patients. Individuals receiving VA inpatient mental health care during the first six months of each fiscal year from 1993 to 1997 were identified from discharge abstracts. A similar cohort of privately insured individuals was identified using MEDSTAT's MarketScan database from 1993 to 1995. Individuals in both cohorts were tracked for six months after discharge. Length of stay, readmission rates, and access to outpatient services were calculated. The private sector outperformed VA on most quality measures, although differences were modest and can likely be explained by the greater severity of illness and social disadvantages of VA patients. Readmission rates increased considerably over time in the private sector, whereas they declined for VA patients. Quality measures varied by diagnosis, with VA performing better than the private sector in treating patients diagnosed with substance abuse and mental disorders not elsewhere classified but worse in treating patients diagnosed with depression. Although the private sector modestly outperformed VA on most quality measures, VA treats a more troubled population, and it improved markedly over time compared with the private sector. As health systems strive to reduce costs of care, methods for comparing and evaluating the quality of care become increasingly important. However, methodological challenges remain substantial.


Comparing methods of quantifying tibial acceleration slope.
Considerable variability in tibial acceleration slope (AS) values, and different interpretations of injury risk based on these values, have been reported. Acceleration slope variability may be due in part to variations in the quantification methods used. Therefore, the purpose of this study was to quantify differences in tibial AS values determined using end points at various percentage ranges between impact and peak tibial acceleration, as a function of either amplitude or time. Tibial accelerations were recorded from 20 participants (21.8 +/- 2.9 years, 1.7 m +/- 0.1 m, 75.1 kg +/- 17.0 kg) during 24 unshod heel impacts using a human pendulum apparatus. Nine ranges were tested from 5-95% (widest range) to 45-55% (narrowest range) at 5% increments. AS(Amplitude) values increased consistently from the widest to narrowest ranges, whereas the AS(Time) values remained essentially the same. The magnitudes of AS(Amplitude) values were significantly higher and more sensitive to changes in percentage range than AS(Time) values derived from the same impact data. This study shows that tibial AS magnitudes are highly dependent on the method used to calculate them. Researchers are encouraged to carefully consider the method they use to calculate AS so that equivalent comparisons and assessments of injury risk across studies can be made.


On the Z-E photoisomerization of chiral 2-pentenoate esters: stationary irradiations, laser-flash photolysis studies, and theoretical calculations.
Chiral pentenoates 1-3 in both Z and E isomeric forms underwent stationary irradiations in several solvents and in the presence of different photosensitizers. The photostationary-state ratio has been determined for each Z/E couple showing a predominance of the thermodynamically more stable isomer for 1 and 3. Moreover, transient species were generated by pulsed laser excitation and detected by their characteristic ultraviolet absorptions, being the first time that enoate-originated triplets are detected. Stern-Volmer quenching studies afforded a quantitative measure for the efficiency of the photosensitization processes induced by benzophenone or acetophenone and allowed the determination of the corresponding quenching rate constants. Density functional calculations permitted the determination of the geometries and the energies of the diastereomeric excited states. Two diastereomeric orthogonal and two diastereomeric planar structures result as a consequence of the presence of a chiral substituent. The orthogonal triplets are the energy minima in all cases, whereas the planar triplets are the transition states linking these orthogonal structures, the corresponding energy barriers being 8-10 kcal mol(-1) for enoates 1-3. The computed S(0) to T(1) excitation energies show a trend which is consistent with the quenching rate constants. On the other hand, the triplet lifetimes determined for 1 and 2 are unusually long (1-20 micros) if compared with the data already described for several enones, in the range of nanoseconds. This fact has been rationalized from calculations of spin-orbit coupling at several points of the T(1) potential energy surface. This coupling is maximum for structures with a torsional angle close to 45 degrees, which are 4-5 kcal mol(-1) above the minima of T(1). Calculations done on the hypothetical aldehyde 4 and methyl vinyl ketone show much lower energy barriers, thus accounting for the shorter lifetimes reported for enone triplets.


Synthesis of carbohydrate derivatives using solid-phase work-up and scavenging techniques.
Methods to allow the clean preparation of oligosaccharides were investigated using techniques that do not require conventional column chromatography or an aqueous work-up. The route was designed to provide rapid access to oligosaccharides and is suitable for automation and parallel library formation. The research has focused on the glycosidations of a range of glycosyl acceptors with various selenophenyl glycosyl donors using iodine as an activator in the presence of DTBMP, a hindered organic base. Hydroxyl-containing contaminants were removed by scavenging with polymer-supported tosyl chloride.


The global burden of mental, neurological and substance use disorders: an analysis from the Global Burden of Disease Study 2010.
The Global Burden of Disease Study 2010 (GBD 2010), estimated that a substantial proportion of the world's disease burden came from mental, neurological and substance use disorders. In this paper, we used GBD 2010 data to investigate time, year, region and age specific trends in burden due to mental, neurological and substance use disorders. For each disorder, prevalence data were assembled from systematic literature reviews. DisMod-MR, a Bayesian meta-regression tool, was used to model prevalence by country, region, age, sex and year. Prevalence data were combined with disability weights derived from survey data to estimate years lived with disability (YLDs). Years lost to premature mortality (YLLs) were estimated by multiplying deaths occurring as a result of a given disorder by the reference standard life expectancy at the age death occurred. Disability-adjusted life years (DALYs) were computed as the sum of YLDs and YLLs. In 2010, mental, neurological and substance use disorders accounted for 10.4% of global DALYs, 2.3% of global YLLs and, 28.5% of global YLDs, making them the leading cause of YLDs. Mental disorders accounted for the largest proportion of DALYs (56.7%), followed by neurological disorders (28.6%) and substance use disorders (14.7%). DALYs peaked in early adulthood for mental and substance use disorders but were more consistent across age for neurological disorders. Females accounted for more DALYs in all mental and neurological disorders, except for mental disorders occurring in childhood, schizophrenia, substance use disorders, Parkinson's disease and epilepsy where males accounted for more DALYs. Overall DALYs were highest in Eastern Europe/Central Asia and lowest in East Asia/the Pacific. Mental, neurological and substance use disorders contribute to a significant proportion of disease burden. Health systems can respond by implementing established, cost effective interventions, or by supporting the research necessary to develop better prevention and treatment options.


Prevalence of high frequency hearing loss consistent with noise exposure among people working with sound systems and general population in Brazil: a cross-sectional study.
Music is ever present in our daily lives, establishing a link between humans and the arts through the senses and pleasure. Sound technicians are the link between musicians and audiences or consumers. Recently, general concern has arisen regarding occurrences of hearing loss induced by noise from excessively amplified sound-producing activities within leisure and professional environments. Sound technicians' activities expose them to the risk of hearing loss, and consequently put at risk their quality of life, the quality of the musical product and consumers' hearing. The aim of this study was to measure the prevalence of high frequency hearing loss consistent with noise exposure among sound technicians in Brazil and compare this with a control group without occupational noise exposure. This was a cross-sectional study comparing 177 participants in two groups: 82 sound technicians and 95 controls (non-sound technicians). A questionnaire on music listening habits and associated complaints was applied, and data were gathered regarding the professionals' numbers of working hours per day and both groups' hearing complaint and presence of tinnitus. The participants' ear canals were visually inspected using an otoscope. Hearing assessments were performed (tonal and speech audiometry) using a portable digital AD 229 E audiometer funded by FAPESP. There was no statistically significant difference between the sound technicians and controls regarding age and gender. Thus, the study sample was homogenous and would be unlikely to lead to bias in the results. A statistically significant difference in hearing loss was observed between the groups: 50% among the sound technicians and 10.5% among the controls. The difference could be addressed to high sound levels. The sound technicians presented a higher prevalence of high frequency hearing loss consistent with noise exposure than did the general population, although the possibility of residual confounding due to unmeasured factors such as socioeconomic status cannot be ruled out.


[The acoustic characteristics of the speech signal as an indicator of the human functional state].
The current review focuses on the capabilities and the efficiency of the functional state investigation based on the extralinguistic (nonsemantic) properties of the speech signal. This article provides an overview of the studies, which used such speech signal characteristics to investigate the human state during performing the operator activity, in the simulation of emotions, under emotional stress and in the presence of various mental disorders.


Separate turnover of cytochrome c and myoglobin in the red types of skeletal muscle.
The purpose of this investigation was to determine whether cytochrome c and myoglobin have similar turnover rates in the three types of skeletal muscles. Exercise (endurance training) was used as an inducing stimulus to increase their concentrations. The half-lives (t 1/2) were subsequently estimated from the time course of return to base-line levels after cessation of exercise. When exercise was stopped, cytochrome c concentration returned rapidly to control levels; the lengths of t 1/2 were approximately 8 days in fast-twitch red, 5 days in slow-twitch red, and 9 days in mixed muscles. These findings confirm previous results of cytochrome c turnover. The concentration of myoglobin decreased at a slower rate than that observed for cytochrome c during detraining in fast-red slow-red, and plantaris muscles, and did not return to sedentary control levels throughout the 50-day detraining period. Myoglobin concentration in fast-twitch white muscle did not increase with the training. These results provide evidence that the degradation rate of myoglobin differs from that of cytochrome c in the red types of skeletal muscle. These elevated myoglobin levels may, in part, provide one explanation for the slow rate of decline in aerobic power that has been observed when individuals stop exercising.


CCK regulates pancreatic enzyme secretion via short duodenal-pancreatic reflexes in pigs.
Different routes of administration of CCK-33 and blockage of CCK-A and muscarinic (m3) receptors are used in this study to evaluate the mechanisms by which cholecystokinin can stimulate the exocrine pancreas. The experiment was performed on eight anaesthetized pigs during control conditions and after administration of the CCK-A and m3 receptor antagonists, Tarazepide and 4-DAMP, respectively. Catheters were surgically implanted in the pancreatic duct for juice collection and in the gastric and right gastro-epipoic arteries and in the jugular vein, so that infusions of CCK-33 could be made exclusively to the duodenum/stomach, duodenum/pancreas or general circulation, respectively. Infusion of a low dose of CCK-33 (13 pmol kg(-1)) to the general circulation did not affect pancreatic protein or trypsin output. When the same dose was given directly to the duodenum/stomach or the duodenum/pancreas, pancreatic output increased during both control conditions and after Tarazepide and/or 4-DAMP treatment, though the increase in trypsin output was lower after Tarazepide and/or 4-DAMP blockade. A high dose of CCK-33 (130 pmol kg(-1)) given peripherally stimulated the pancreatic secretion, but this response was totally abolished in Tarazepide and 4-Damp treated animals. Pancreatic enzyme secretion due to CCK-33 stimulation depends on the presence of short duodenal-pancreatic peptidergic reflexes evoked mainly via low sensitive, probably CCK-B, receptors located in the duodenum/stomach. Pancreatic secretion evoked by peripheral CCK-33 in pharmacological doses was independent of m3 receptors blockade but depended on CCK-A receptors located elsewhere than in the duodenum/pancreas.


Scrapie prion proteins accumulate in the cytoplasm of persistently infected cultured cells.
The cellular prion protein (PrPC) is a sialoglycoprotein anchored to the external surface of cells by a glycosyl phosphatidylinositol moiety. During scrapie, an abnormal PrP isoform designated PrPSc accumulates, and much evidence argues that it is a major and necessary component of the infectious prion. Based on the resistance of native PrPSc to proteolysis and to digestion with phosphatidylinositol-specific phospholipase C as well as the enhancement of PrPSc immunoreactivity after denaturation, we devised in situ immunoassays for the detection of PrPSc in cultured cells. Using these immunoassays, we identified the sites of PrPSc accumulation in scrapie-infected cultured cells. We also used these immunoassays to isolate PrPSc-producing clones from a new hamster brain cell line (HaB) and found an excellent correlation between their PrPSc content and prion infectivity titers. In scrapie-infected HaB cells as well as in scrapie-infected mouse neuroblastoma cells, most PrPSc was found to be intracellular and most localized with ligands of the Golgi marker wheat germ agglutinin. In one scrapie-infected HaB clone, PrPSc also localized extensively with MG-160, a protein resident of the medial-Golgi stack whereas this colocalization was not observed in another subclone of these cells. Whether the sites of intracellular accumulation of PrPSc are limited to a few subcellular organelles or they are highly variable remains to be determined. If the intracellular accumulation of PrPSc is found in the cells of the central nervous system, then it might be responsible for the neuronal dysfunction and degeneration which are cardinal features of prion diseases.


Monitoring dithiocarbamate fungicide residues in greenhouse and non-greenhouse tomatoes in Iran by HPLC-UV.
The simultaneous analysis of dithiocarbamate fungicide residues on greenhouse and non-greenhouse tomatoes was performed by high-performance liquid chromatography with UV detection. A calibration curve with spiked samples was plotted to determine dithiocarbamate residues in tomato samples. Limits of detection and quantification were approximately 0.05 and 0.2 µg g(-1), respectively. The ranges of mean recoveries at five spiking levels for all dithiocarbamates of interest were between 88.2%-95.7% and 99.5%-100.8% in standards and spiked samples, respectively. In this study, 40 greenhouse and 40 non-greenhouse tomato samples were analysed. None of the samples analysed contained dithiocarbamates in excess of the maximum residue levels established by the Codex Committee on Pesticide Residues, except for one greenhouse sample, with ethylenebisdithiocarbamates at 3.2 µg g(-1).


The Lévy flight foraging hypothesis in a pelagic seabird.
Lévy flight foraging represents an innovative paradigm for the analysis of animal random search by including models of heavy-tailed distribution of move length, which complements the correlated random walk paradigm that is founded on Brownian walks. Theory shows that the efficiency of the different foraging tactics is a function of prey abundance and dynamics with Lévy flight being especially efficient in poor prey fields. Lévy flights have been controversial in some quarters, because they previously have been wrongly ascribed to many species through the employment of inappropriate statistical techniques and by misunderstanding movement pattern data. More recent studies using state-of-the-art statistical tools have, however, provided seemingly compelling evidence for Lévy flights. In this study, we employ these maximum-likelihood methods and their Bayesian equivalents by analysing both turning angles and move length distributions. We tested, for compliance with Lévy flight foraging, a set of 77 independent foraging trajectories of Cory's shearwaters Calonectris diomedea diomedea. Birds were tagged with high-resolution GPS loggers in two Mediterranean colonies (Linosa and Tremiti) during both incubation and chick rearing. We found that the behaviour of six birds was fitted by a correlated random walk; the movement of 32 birds was better represented by adaptive correlated random walks by switching from intensive to extensive searches; and the trajectories of 36 birds were fitted by a Lévy flight pattern of movement. The probability of performing Lévy flights was higher for trips during chick provisioning when shearwaters were forced to forage in suboptimal areas. This study supports Lévy flight foraging as an appropriate framework to analyse search tactics in this pelagic bird species and highlights that the adoption of a given search strategy is a function of biological and ecological constraints.


Comparison of mosquito control programs in seven urban sites in Africa, the Middle East, and the Americas.
Mosquito control programs at seven urban sites in Kenya, Egypt, Israel, Costa Rica, and Trinidad are described and compared. Site-specific urban and disease characteristics, organizational diagrams, and strengths, weaknesses, obstacles and threats (SWOT) analysis tools are used to provide a descriptive assessment of each mosquito control program, and provide a comparison of the factors affecting mosquito abatement. The information for SWOT analysis is collected from surveys, focus-group discussions, and personal communication. SWOT analysis identified various issues affecting the efficiency and sustainability of mosquito control operations. The main outcome of our work was the description and comparison of mosquito control operations within the context of each study site's biological, social, political, management, and economic conditions. The issues identified in this study ranged from lack of inter-sector collaboration to operational issues of mosquito control efforts. A lack of sustainable funding for mosquito control was a common problem for most sites. Many unique problems were also identified, which included lack of mosquito surveillance, lack of law enforcement, and negative consequences of human behavior. Identifying common virtues and shortcomings of mosquito control operations is useful in identifying "best practices" for mosquito control operations, thus leading to better control of mosquito biting and mosquito-borne disease transmission.


Oxytocin during labour and risk of severe postpartum haemorrhage: a population-based, cohort-nested case-control study.
Objectives Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental studies support the hypothesis that oxytocin administration during labour, a common although not evidence-based practice, may increase the risk of atonic PPH. The clinical studies, however, are inconclusive. The objectives of this study was to investigate the association between the level of oxytocin exposure during labour and the risk of severe PPH and to explore whether the prophylactic use of oxytocin after birth modifies this association. Design Population-based, cohort-nested case-control study. Setting 106 French hospitals from December 2004 through November 2006. Participants Women with term singleton vaginal deliveries, after an uncomplicated pregnancy. Cases were 1483 women with severe PPH, defined by peripartum change in haemoglobin of ≥4 g/dl or need for blood transfusion. Controls were 1758 women from a random sample of parturients without PPH. Main outcome measures The independent association between the level of oxytocin during labour and the risk of severe PPH was tested and quantified with ORs through two-level multivariable logistic regression modelling. Results Oxytocin was administered during labour to 73% of cases and 61% of controls (crude OR: 1.7, 95% CI 1.5 to 2.0). After adjustment for all potential confounders, oxytocin during labour was associated with a significantly higher risk of severe PPH (adjusted OR: 1.8, 95% CI 1.3 to 2.6) in women who did not receive prophylactic oxytocin after delivery; the OR for haemorrhage increased from 1 to 5 according to the level of oxytocin exposure. In women who had prophylactic oxytocin after delivery, this association was significant only for the highest exposure categories. Conclusions Oxytocin during labour appears to be an independent risk factor for severe PPH. The results emphasise the need for guidelines clarifying the evidence-based indications for this procedure and the minimal useful regimens.


ACC/AHA Special Report: Clinical Practice Guideline Implementation Strategies: A Summary of Systematic Reviews by the NHLBI Implementation Science Work Group: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation.


[2 unusual cases of early embryogenesis].
Two unusual cases of early embryogenesis are described: a giant cleaving egg and the presence of two generations of embryos in the genital tract of a female--at the stage of implantation and at the stage of two blastomeres. The ability of development of the second generation was tested in vitro experiments.


Assessment of left ventricular mechanics in patients with asymptomatic aortic regurgitation: a two-dimensional echocardiographic study.
We describe a noninvasive method for determining end-systolic meridional and circumferential wall stress and left ventricular architecture as the ratio of muscle to cavity area. With this technique, which uses two-dimensional echocardiography and cuff-determined values for systolic blood pressure, we assessed wall stress and left ventricular architecture in 15 normal subjects and 15 asymptomatic patients with severe chronic aortic regurgitation at rest and after load manipulations with sublingual nitroglycerin. Resting end-systolic meridional and circumferential stress were increased in patients with aortic regurgitation (113.9 +/- 29 and 260 +/- 50.7 X 10(3) dynes/cm2) compared with those in normal subjects (85.6 +/- 15.4 and 214.1 +/- 28.4 X 10(3) dynes/cm2) (both p less than .01) and remained significantly greater after nitroglycerin. Meridional stress values obtained from two-dimensional echocardiographic studies correlated closely (r = .89) with values calculated from simultaneously recorded M mode echocardiograms. Ejection fraction in patients with aortic regurgitation and normal subjects were similar at rest (55 +/- 10% vs 59 +/- 6%) and were unchanged by nitroglycerin. In spite of the increased left ventricular mass in patients with aortic regurgitation (227 +/- 60 g vs 130 +/- 22 g in normal subjects), the mass-to-volume ratio and the ratio of muscle to cavity area in diastole in patients with aortic regurgitation were significantly lower than normal (0.90 +/- 0.23 vs 1.30 +/- 0.21 and 0.91 +/- 0.23 vs 1.11 +/- 0.18 [p less than .005 and p less than .02]). These differences were exaggerated after nitroglycerin, while concomitant changes in relative wall thickness were virtually undetected by M mode echocardiography. Thus this technique can be used for early recognition of afterload excess and changes in left ventricular architecture in patients with aortic regurgitation. Furthermore, the mean slopes of the circumferential stress-diameter and meridional stress-length lines, which represent load-independent indexes of myocardial contractile state, could be assessed and were similar in the group of patients with asymptomatic aortic regurgitation and normal subjects, indicating that overall myocardial contractility was still normal. We conclude that circumferential and meridional wall stress, myocardial contractility, and left ventricular architecture can be determined noninvasively. These measurements may prove to be useful in assessing patients with primary myocardial or valvular heart disease and determining their long-term management.


Expression of HuD (a paraneoplastic encephalomyelitis antigen) mRNA in lung cancer.
HuD, one of the Hu antigens (HuD and HuC), was recognized in the sera of small cell lung cancer (SCLC) patients with antibody-associated paraneoplastic encephalomyelitis/peripheral sensory neuropathy (PEM/PSN). Three forms of HuD mRNA, 197, 156, 110 nucleotides are made by alternative splicing at 868-909 residues and an additional 3'-splice site. To determine the diagnostic value of the HuD expression for small cell lung cancer, we examined 4 SCLC cell lines, 9 surgically resected SCLCs, and 12 surgically resected non-SCLCs using the reverse transcriptase-polymerase chain reaction with the HuD-specific primer pairs that spanned the putative alternative 3'-splicing site and direct DNA sequencing. None of the patients were associated with PEM/PSN. A single RNA transcript (156 nucleotides) among three forms (110, 156, 197 nucleotides) of the HuD gene was an alternatively spliced at 868-909 residues in SCLC cell lines. Expression of the HuD gene was stronger in three classic cell lines, but not in a variant cell line. Two of 9 SCLCs (22%) and 3 of 12 non-SCLCs (25%) expressed only the major RNA transcript (156 nucleotides) of the HuD gene, which was alternatively spliced in the same fashion as the cell line. These results revealed that no aberrant alternative splicing occurred in SCLC not associated with PEM/PSN and the expression of HuD gene was not specific for a particular histologic subtype of human lung cancer.


Associations between meal and snack frequency and overweight and abdominal obesity in US children and adolescents from National Health and Nutrition Examination Survey (NHANES) 2003-2012.
The association between eating frequency (EF) and adiposity in young populations is inconsistent. This cross-sectional study examined associations of EF, meal frequency (MF) and snack frequency (SF) with adiposity measures in US children aged 6-11 years (n 4346) and adolescents aged 12-19 years (n 6338) participating in the National Health and Nutrition Examination Survey 2003-2012. Using data from two 24-h dietary recalls, all eating occasions providing ≥210 kJ of energy were divided into meals or snacks based on contribution to energy intake (≥15 or <15 %), self-report and time (06.00-09.00, 12.00-14.00 and 17.00-20.00 hours or others). When analysed without adjustment for the ratio of reported energy intake:estimated energy requirement (EI:EER), all measures of EF, MF and SF showed inverse or null associations with overweight (BMI≥85th percentile of BMI-for-age) and abdominal obesity (waist circumference≥90th percentile) in both children and adolescents. After adjustment for EI:EER, however, EF and SF, but not MF, showed positive associations in children, irrespective of the definition of meals and snacks. In adolescents, after adjustment for EI:EER, positive associations were observed for EF (abdominal obesity only), SF based on energy contribution and MF based on self-report, whereas there was an inverse association between MF based on energy contribution and overweight. In conclusion, higher SF and EF, but not MF, were associated with higher risks of overweight and abdominal obesity in children, whereas associations varied in adolescents, depending on the definition of meals and snacks. Prospective studies are needed to establish the associations observed here.


Early Palliative Care Is Associated With Reduced Emergency Department Utilization in Pancreatic Cancer.
Most patients with pancreatic cancer have high symptom burden and poor outcomes. Palliative care (PC) can improve the quality of care through expert symptom management, although the optimal timing of PC referral is still poorly understood. We aimed to assess the association of early PC on health care utilization and charges of care for pancreatic cancer patients. We selected patients with pancreatic cancer diagnosed between 2000 and 2009 who received at least 1 PC encounter using the Surveillance, Epidemiology, and End Results (SEER)-Medicare. Patients who had unknown follow-up were excluded. We defined "early PC" if the patients received PC within 30 days of diagnosis. A total of 3166 patients had a PC encounter; 28% had an early PC. Patients receiving early PC were more likely to be female and have older age compared with patients receiving late PC (P<0.001). Patients receiving early PC had fewer emergency department (ED) visits (2.6 vs. 3.0 visits, P=0.004) and lower total charges of ED care ($3158 vs. $3981, P<0.001) compared with patients receiving late PC. Patients receiving early PC also had lower intensive care unit admissions (0.82 vs. 0.98 visits, P=0.006) and total charges of intensive care unit care ($14,466 vs. $18,687, P=0.01). On multivariable analysis, patients receiving early PC were significantly associated with fewer ED visits (P=0.007) and lower charges of ED care (P=0.018) for all patients. Early PC referrals were associated with lower ED visits and ED-related charges. Our findings support oncology society guideline recommendations for early PC in patients with advanced malignancies such as pancreatic cancer.


The effect of a distance-delivered mindfulness-based psychoeducation program on the psychological well-being, emotional intelligence and stress levels of nursing students in Turkey: a randomized controlled study.
Nursing students who started university during the COVID-19 pandemic had to attend via distance education, which increased their stress. This study aimed to determine the effect of a mindfulness-based psychoeducation program on the psychological well-being, emotional intelligence and stress levels of young adults in their first year of an undergraduate nursing program at a university in Turkey. The sample consisted of 59 students (mean age 19.3 years) who were randomized to the intervention group (n = 29) and control group (n = 30). Those in the intervention group participated in a mindfulness-based psychoeducation program twice a week for 4 weeks via video conference. The Perceived Stress Scale (PSS-14), Psychological Well-Being Scale (PWB) and Revised Schutte Emotional Intelligence Scale (SEIS) were used as measurement tools. Between the pretest and posttest assessments, students in the intervention group showed a significant decrease in perceived stress scores and increases in emotional intelligence and psychological well-being scores. There were statistically significant differences in perceived stress, emotional intelligence and psychological well-being scores between the intervention and control groups in the posttest. Online mindfulness psychoeducation via video conferencing can be a useful intervention for nursing students to reduce stress and support psychological well-being and emotional intelligence.


Impact and influences on caregiver outcomes at one year post-stroke.
Four outcome measures of carer stress and coping at one year post-stroke were identified: carer general health, anxiety, depression and perception of stress. Each outcome was assessed using valid and reliable instruments. In addition, we collected demographic data from both carers and patients which could reasonably be expected to influence carer stress and coping (e.g. age, deprivation levels) as well as information specific to the caring role. Carers were found to be more anxious than previously reported. Neither satisfaction with caring nor the adoption of helpful coping strategies were associated with positive carer outcomes but, nevertheless, carers were not reluctant to care. The SF-36 is a useful predictor of carer stress, in particular the vitality score. Patient data are not sufficient to predict carer general health at one year. At one year, both patients and carers are more anxious than depressed. And there may be a group of patients and carers who can be characterised as borderline anxious and/or depressed and who warrant specific attention to prevent carer burnout.


Structural elucidation and quantification of phenolic conjugates present in human urine after tea intake.
In dietary polyphenol exposure studies, annotation and identification of urinary metabolites present at low (micromolar) concentrations are major obstacles. To determine the biological activity of specific components, it is necessary to have the correct structures and the quantification of the polyphenol-derived conjugates present in the human body. We present a procedure for identification and quantification of metabolites and conjugates excreted in human urine after single bolus intake of black or green tea. A combination of a solid-phase extraction (SPE) preparation step and two high pressure liquid chromatography (HPLC)-based analytical platforms was used, namely, accurate mass fragmentation (HPLC-FTMS(n)) and mass-guided SPE-trapping of selected compounds for nuclear magnetic resonance spectroscopy (NMR) measurements (HPLC-TOFMS-SPE-NMR). HPLC-FTMS(n) analysis led to the annotation of 138 urinary metabolites, including 48 valerolactone and valeric acid conjugates. By combining the results from MS(n) fragmentation with the one-dimensional (1D)-(1)H NMR spectra of HPLC-TOFMS-SPE-trapped compounds, we elucidated the structures of 36 phenolic conjugates, including the glucuronides of 3',4'-di- and 3',4',5'-trihydroxyphenyl-γ-valerolactone, three urolithin glucuronides, and indole-3-acetic acid glucuronide. We also obtained 26 h-quantitative excretion profiles for specific valerolactone conjugates. The combination of the HPLC-FTMS(n) and HPLC-TOFMS-SPE-NMR platforms results in the efficient identification and quantification of less abundant phenolic conjugates down to nanomoles of trapped amounts of metabolite corresponding to micromolar metabolite concentrations in urine.


Differential expression of microsomal prostaglandin e synthase at implantation sites and in decidual cells of mouse uterus.
Prostaglandin E(2) (PGE(2)) is considered important for blastocyst spacing, implantation, and decidualization in the rodent uterus. PGE synthase (PGES) catalyzes the isomerization of PGH(2) to PGE(2). There are two isoforms of PGES, microsomal PGES (mPGES) and cytosolic PGES (cPGES). However, the expression and regulation of mPGES in the mammalian uterus during early pregnancy are still unknown. The aim of this study was to investigate the differential expression of mPGES in mouse uterus during early pregnancy and its regulation under different conditions by in situ hybridization and immunohistochemistry. Microsomal PGES expression in the preimplantation mouse embryos was also performed by reverse transcription polymerase chain reaction (RT-PCR). Expression of mPGES mRNA and protein was at a basal level in the luminal epithelium from Day 1 to Day 4 of pregnancy. However, mPGES mRNA and protein were highly expressed in the stroma immediately surrounding the blastocyst but not in the luminal epithelium on Day 5 of pregnancy. Microsomal PGES mRNA and protein were not detected in the pseudopregnant uterus from Day 1 to Day 5. During delayed implantation, mPGES mRNA and protein were also not detected in the uterus. Once delayed implantation was terminated by estrogen treatment and embryo implantation initiated, both mPGES mRNA and protein were induced to express in the stroma immediately surrounding the blastocyst, which was similar to the expression pattern on Day 5 of pregnancy. From Day 6 to Day 8 of pregnancy, the signals for mPGES mRNA and protein were strongly detected in the decidualized cells. Microsomal PGES mRNA and protein were also highly expressed in the artificially decidualized cells but not in the control horn. Microsomal PGES mRNA was detected in the oocytes and all the stages of preimplantation embryos. The strong mPGES expression in the implantation site and decidual cells suggests that mPGES might play an important role during implantation and more importantly in decidualization.


The Impact of Emotion on Musical Long-Term Memory.
The influence of emotional dimensions such as arousal and valence on memory has been a topic of particularly intense inquiry. As stimuli go, music is capable of provoking strong emotional responses from listeners, which can in turn influence memory. However, few studies have examined the effect of musical emotions on memory, and even fewer the effect of valence and arousal. In order to shed light on the ways in which emotional dimensions affect musical memory as study-test delay intervals increase, we tested recognition after a short delay and after a long delay. In line with the literature, we hypothesized an emotional enhancement of music memory induced by post-encoding processes leading to better recognition of musical excerpts in delayed condition, as compared to the immediate condition. The effects of arousal and valence were expected to become exaggerated after a long delay. We also predicted that the two emotional dimensions would be differently affected by the study-test intervals. Our results showed that the emotional enhancement of memory depends upon the valence, with remembering of positive and negative stimuli being differently affected by the duration of the study-test delay interval. Furthermore, our data demonstrated that musical excerpts were better recognized after a long delay than after a short delay, illustrating that memory consolidation for musical information is taking place during the long study-test interval. Moreover, musical memory consolidation is strongly related to the characteristics of the positive valence, which have been discussed in relation to its pleasantness. This original finding provides new insights into the modulatory effects of emotional valence on memory consolidation and could offer promising therapeutic possibilities for the rehabilitation of memory disorders.


Effect of yohimbine on rat prolactin secretion.
It was recently proposed that yohimbine (YOH), an indole alkaloid with multiple pharmacological effects, is an antagonist of the D2 dopamine (DA) receptor. Because the pituitary DA receptor involved in the inhibition of prolactin (PRL) secretion is the prototypic D2 receptor, we examined the effect of YOH on PRL secretion in male rats. YOH produced marked, dose-dependent and sustained increases in plasma PRL levels. However, YOH did not block the inhibitory effect of DA on PRL release from rat pituitary glands in vitro, did not displace [3H]spiperone from bovine pituitary membranes and had no effect on the concentration of DA in pituitary stalk plasma of anesthetized rats, suggesting that the stimulation of PRL release by YOH is not due to its antidopaminergic effects. Clonidine, an alpha-2 adrenergic agonist, produced a partial, non-dose-dependent inhibition of the YOH-induced rise in serum PRL levels. Two antagonists of the H1 histamine receptor, diphenhydramine and promethazine, markedly antagonized the PRL-releasing effect of YOH, but another H1 blocker, chlorpheniramine, and an H2 antagonist, metiamide, had no effect. Serotonin receptor blockers, cyproheptadine, mianserin and pizotifen, and the opiate antagonist, naloxone, also had no effect on the PRL response to YOH. Nevertheless, the PRL-releasing effect of YOH was potentiated 24 hr after the administration of reserpine or para-chlorophenylalanine, an inhibitor of serotonin synthesis. Thus, the mechanisms by which YOH stimulates rat PRL secretion has has not been fully elucidated. It is possible that YOH may stimulate PRL secretion by a novel mechanism, possibly through the intervention of a PRL-releasing factor.


Isolation of a novel member of small G protein superfamily and its expression in colon cancer.
APMCF1 is a novel human gene whose transcripts are up-regulated in apoptotic MCF-7 cells. In order to learn more about this gene's function in other tumors, we cloned its full length cDNA and prepared its polyclonal antibody to investigate its expression in colon cancers with immunohistochemistry. With the method of 5' rapid amplification of cDNA end (RACE) and EST assembled in GenBank, we extended the length of APMCF1 at 5' end. Then the sequence encoding the APMCF1 protein was amplified by RT-PCR from the total RNA of apoptotic MCF-7 cells and cloned into the prokaryotic expression vector pGEX-KG to construct recombinant expression vector pGEX-APMCF1. The GST-APMCF1 fusion protein was expressed in E. coli and used to immunize rabbits to get the rabbit anti-APMCF1 serum. The specificity of polyclonal anti-APMCF1 antibody was determined by Western blot. Then we investigated the expression of Apmcf1 in colon cancers and normal colonic mucosa with immunohistochemistry. A cDNA fragment with a length of 1 745 bp was obtained. APMCF1 was mapped to chromosome 3q22.2 and spanned at least 14.8 kb of genomic DNA with seven exons and six introns contained. Bioinformatic analysis showed the protein encoded by APMCF1 contained a small GTP-binding protein (G proteins) domain and was homologous to mouse signal recognition particle receptor beta(SRbeta). A coding region covering 816 bp was cloned and polyclonal anti-APMCF1 antibody was prepared successfully. The immunohistochemistry study showed that APMCF1 had a strong expression in colon cancer. APMCF1 may be the gene coding human signal recognition particle receptor beta and belongs to the small-G protein superfamily. Its strong expression pattern in colon cancer suggests it may play a role in colon cancer development.


Effects of major depression, aging and gender upon calculated diurnal free plasma cortisol concentrations: a re-evaluation study.
Depression, aging and female gender are associated with increased diurnal concentrations of total plasma cortisol. For the physical effects of hypercortisolemia, however, it is generally assumed that free rather than total plasma cortisol concentrations are of importance. Herein, we report a mathematical approach to determine free plasma cortisol concentrations on the basis of total cortisol, corticosteroid binding-globulin (CBG) and albumin plasma concentrations. This approach was used to re-evaluate two sets of data in order to estimate the effect of depression as well as the effect of aging and gender upon free plasma cortisol concentrations. Comparing male depressed patients with healthy controls, we found 24-hour free cortisol minima (MIN: 4.1 +/- 1.8 vs. 1.6 +/- 1.1 nmol/l, p < 0.0001), mean (MEAN: 25.5 +/- 6.7 vs. 10.4 +/- 2.7 nmol/l, p < 0.0001) and maximal (MAX: 85.3 +/- 23.3 vs. 45.2 +/- 15. 8 nmol/l, p < 0.0001) concentrations to be significantly increased in depressed patients. In general, the impact of depression upon total plasma cortisol were not only maintained, but stronger regarding free plasma cortisol. Also, age was associated with free plasma cortisol MIN (F1,30= 10.8, p < 0.003) and free plasma cortisol MEAN (F1,30 = 8.9, p < 0.006). All effects of age upon total plasma cortisol were generally also found in free plasma cortisol, though with less impact. No effect of gender upon any of the given free plasma cortisol outcome variables was found. Taken together, our re-evaluation clearly shows not only depression but also aging to be associated with increases in free plasma cortisol concentrations. This finding is in line with the observation that in both conditions medical problems triggered and/or maintained by glucocorticoids (e.g. osteoporosis) are frequently seen.


Impact of a novel phosphoinositol-3 kinase inhibitor in preventing mitochondrial DNA damage and damage-associated molecular pattern accumulation: Results from the Biochronicity Project.
Despite improvements in the management of severely injured patients, development of multiple organ dysfunction syndrome (MODS) remains a morbid complication of traumatic shock. One of the key attributes of MODS is a profound bioenergetics crisis, for which the mediators and mechanisms are poorly understood. We hypothesized that metabolic uncoupling using an experimental phosphoinositol-3 kinase (PI3-K) inhibitor, LY294002 (LY), may prevent mitochondrial abnormalities that lead to the generation of mitochondrial DNA (mtDNA) damage and the release of mtDNA damage-associated molecular patterns (DAMPs). Sixteen swine were studied using LY, a nonselective PI3-K inhibitor. Animals were assigned to trauma only (TO, n = 3), LY drug only (LYO, n = 3), and experimental (n = 10), trauma + drug (LY + T) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia-reperfusion injury, and protocolized resuscitation. A battery of hemodynamic, laboratory, histological, and bioenergetics parameters were monitored. Mitochondrial DNA damage was determined in lung, liver, and kidney using Southern blot analyses, whereas plasma mtDNA DAMP analysis used polymerase chain reaction amplification of a 200-bp sequence of the mtDNA D-loop region. Relative to control animals, H + I/R (hemorrhage and ischemia/reperfusion) produced severe, time-dependent decrements in hepatic, renal, cardiovascular, and pulmonary function accompanied by severe acidosis and lactate accumulation indicative of bioenergetics insufficiency. The H-I/R animals displayed prominent oxidative mtDNA damage in all organs studied, with the most prominent damage in the liver. Mitochondrial DNA damage was accompanied by accumulation of mtDNA DAMPs in plasma. Pretreatment of H + I/R animals with LY resulted in profound metabolic suppression, with approximately 50% decreases in O2 consumption and CO2 production. In addition, it prevented organ and bioenergetics dysfunction and was associated with a significant decrease in plasma mtDNA DAMPs to the levels of control animals. These findings show that H + I/R injury in anesthetized swine is accompanied by MODS and by significant mitochondrial bioenergetics dysfunction, including oxidative mtDNA damage and accumulation in plasma of mtDNA DAMPs. Suppression of these changes with the PI3-K inhibitor LY indicates that pharmacologically induced metabolic uncoupling may comprise a new pharmacologic strategy to prevent mtDNA damage and DAMP release and prevent or treat trauma-related MODS. Therapeutic study, level III.


PCET-Enabled Olefin Hydroamidation Reactions with N-Alkyl Amides.
Olefin aminations are important synthetic technologies for the construction of aliphatic C-N bonds. Here we report a catalytic protocol for olefin hydroamidation that proceeds through transient amidyl radical intermediates that are formed via proton-coupled electron transfer (PCET) activation of the strong N-H bonds in N-alkyl amides by an excited-state iridium photocatalyst and a dialkyl phosphate base. This method exhibits a broad substrate scope, high functional group tolerance, and amenability to use in cascade polycyclization reactions. The feasibility of this PCET protocol in enabling the intermolecular anti-Markovnikov hydroamidation reactions of unactivated olefins is also demonstrated.


Passive inhalation of marihuana smoke and urinary excretion of cannabinoids.
Three studies in which exposure to marihuana smoke was progressively increased were conducted. In each, four experienced marihuana users smoked marihuana cigarettes in the presence of two nonsmoking subjects. They were confined in a closed environment for 1 hr after the smoking began. All urine voided by the nonsmoking subjects was collected separately for 24 hr and analyzed for the presence of cannabinoids by the enzyme multiplied radioimmunoassay technique (EMIT) cannabinoid assay. Blood samples were drawn from one of the nonsmoking subjects in one of the studies, and delta 9-tetrahydrocannabinol (THC) plasma concentrations were determined by radioimmunoassay. The results obtained indicate that of 80 urine samples collected in the three studies, the drug levels in only two slightly exceeded the value of 20 ng/ml on the calibrator of the EMIT assay. Minute but detectable concentrations were present in the plasma of the one subject from whom blood samples were obtained. In this subject intravenous infusion of THC at the rate of 3.2 micrograms/min for 1 hr resulted in THC plasma concentrations identical to those during his passive inhalation of marihuana smoke.


Neuropeptidomics of the mosquito Aedes aegypti.
Neuropeptidomic data were collected on the mosquito Ae. aegypti, which is considered the most tractable mosquito species for physiological and endocrine studies. The data were solely obtained by direct mass spectrometric profiling, including tandem fragmentation, of selected tissues from single specimens, which yielded a largely complete accounting of the putative bioactive neuropeptides; truncated neuropeptides with low abundance were not counted as mature peptides. Differential processing within the CNS was detected for the CAPA-precursor, and differential post-translational processing (pyroglutamate formation) was detected for AST-C and CAPA-PVK-2. For the first time in insects, we succeeded in the direct mass spectrometric profiling of midgut tissue which yielded a comprehensive and immediate overview of the peptides involved in the endocrine system of the gut. Head peptides which were earlier identified as the most abundant RFamides of Ae. aegypti, were not detected in any part of the CNS or midgut. This study provides a framework for future investigations on mosquito endocrinology and neurobiology. Given the high sequence similarity of neuropeptide precursors identified in other medically important mosquitoes, conclusions regarding the peptidome of Ae. aegypti likely are applicable to these mosquitoes.


VGKC antibodies in pediatric encephalitis presenting with status epilepticus.
Voltage-gated potassium channel antibodies (VGKC Ab) are associated with limbic encephalitis and neuromyotonia in adults. There have been no systematic investigations in children to date. We looked for antibodies that are associated with CNS syndromes in adults including antibodies to VGKCs, NMDARs, glutamic acid decarboxylase (GAD), and glycine receptor (GlyR) in the stored acute serum from 10 children with unexplained encephalitis presenting with encephalopathy and status epilepticus. We also looked for antibodies to leucine-rich glioma-inactivated 1 (Lgi1) and contactin-associated protein-like 2 (Caspr2), which are now known to be tightly complexed with VGKCs in vivo. Sixty-nine pediatric controls were used for comparison. An elevated VGKC Ab (>100 pM) was detected in 4/10 patients with encephalitis compared to only 1/69 controls (p < 0.001). The outcome in the 4 VGKC Ab-positive patients with encephalitis was variable including good recovery (n = 1), cognitive impairment (n = 3), temporal lobe epilepsy (n = 2), and mesial temporal sclerosis (n = 1). No other antibodies were detected, including those to Lgi1 and Caspr2. Encephalitis associated with VGKC Ab occurs in children and presents with status epilepticus and focal epilepsy. These antibodies are not directed against Lgi1 or Caspr2.


[Influence of polyethylene oxide Polyox WSR-301 on the pressure in mesenteric arterial microvessels in rats pre-adapted to anti-orthostatic states].
High-molecular polymers apt to directly influence flow microstructure were tested as a fundamentally new method for correcting microhemodynamics in microgravity. Pressure in the mesenteric arterial microvessels was measured two weeks in rats adapted to the head-down suspension. Intravenous polyethylene oxide (Polyox WSR-301, end-concentration in the order of 2.10(-7) g/ml), reduced the microvascular pressure by 26%, whereas in the control pressure was reduced by only 15%. Systemic arterial pressure showed an equal drop in the groups (by 10 to 11%). These results suggest that the biomechanical agent weakens resistance to the blood flow in the body region where blood supply is impaired by microgravity.


[Lutzomyia whitmani periurbanization in a focus of cutaneous leishmaniasis in the State of Maranhão, Brazil].
An entomological survey was performed in the periurban area of the municipality of Dom Pedro in the state of Maranhão in 2000, in order to estimate the abundance of Lutzomyia longipalpis, due to the occurrence of one suspect death caused by kala azar. However, it was surprisingly verified that 82.4% (2,440 specimens) from the total of 2,961 sand flies captured in the peridomicile were Lutzomyia whitmani. This association has indicated a new pattern for cutaneous leishmaniasis transmission (urban), as has been observed with regard to kala azar in the northeast of Brazil.


Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies.
Histopathologic diagnosis of endometrial biopsies is used to estimate the risk of progression to carcinoma and guide clinical management. Problems with the widely used World Health Organization (WHO) system for classifying endometrial hyperplasia (EH) have prompted the development of an alternative system based on endometrial intraepithelial neoplasia (EIN). The authors estimated progression risk associated with EIN among endometrial biopsies in a nested case-control study of EH progression. Index biopsies with original community pathology diagnoses of disordered proliferative endometrium (DPEM) or EH that were independently confirmed by a panel of pathologists were independently reviewed and assigned EIN classifications (inadequate, benign, EIN, or cancer) by a second panel of pathologists. Cases (N = 138) progressed to carcinoma at least 1 year (median, 6 years) after their index biopsy. Controls (N = 241) also had EH, did not progress to carcinoma, and were individually matched to cases based on age at EH, date of EH, and length of follow-up. By using conditional logistic regression, the authors estimated relative risks (RRs) with 95% confidence intervals (95% CIs) for progression to carcinoma for EIN versus benign. In the EIN system, 71 (52.6%) cases and 159 (66.8%) controls were classified as benign and 42 (31.1%) cases and 65 (27.3%) controls were classified as EIN. The RR for EIN versus benign was 7.76 (95% CI, 3.36-17.91). In the WHO system, the RR for atypical hyperplasia (AH) versus DPEM, simple hyperplasia, or complex hyperplasia was 9.19 (95% CI, 3.87-21.83). Among women observed for at least 1 year after receiving a biopsy-based EH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinoma.


Effects of Automated Messages on Internet Users Attempting to Access "Barely Legal" Pornography.
With the increasing number of individuals accessing online child sexual exploitation material (CSEM), there is an urgent need for primary prevention strategies to supplement the traditional focus on arrest and prosecution. We examined whether online warning messages would dissuade individuals from visiting a honeypot website purporting to contain barely legal pornography. Participants (n = 419) seeking the site were randomly assigned to one of five conditions; they went straight to the landing page (control; n = 100) or encountered a warning message advising of the potential harm to viewers (n = 74), potential harm to victims (n = 65), ability of police to track IP addresses (n = 81), or possible illegality of such pornography (n = 99). We measured the attempted click-through to the site. Attrition rates for the warning message conditions were 38% to 52%, compared with 27% for the control group. The most effective messages were those that warned that IP addresses can be traced (odds ratio [OR] = 2.64) and that the pornography may be illegal (OR = 2.99). We argue that warning messages offer a valuable and cost-effective strategy that can be scaled up to help reduce the accessing of CSEM online.


On the Role of Central Type-1 Cannabinoid Receptor Gene Regulation in Food Intake and Eating Behaviors.
Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.


Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause.
The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.


The effect of different types of stressors during mid- and late pregnancy on lamb weight and body size at birth.
Mid-pregnancy shearing has consistently been shown to increase lamb birth weight, which can lead to an increase in lamb survival rates. However, shearing ewes during the winter months and under outdoor pastoral farming conditions can expose the recently shorn ewe to a greater risk of hypothermia. The aim of this study was to determine if exposure of ewes to repeated stressors, in mid- and late pregnancy, would result in an increase in lamb birth weight. This information may assist in the elucidation of the mechanism for the birth weight response to mid-pregnancy shearing, which in turn could assist in the design of management options to increase lamb birth weight without placing the ewe at risk. One hundred and forty-four twin-bearing Romney ewes were allocated to one of six mid-pregnancy treatments: control, isolation on 2 or 10 occasions, sham-shearing on 10 occasions, intramuscular cortisol injection on 10 occasions or shearing. Isolation, sham-shearing and cortisol treatments were conducted twice a week beginning, on average, day 74 of pregnancy and shearing occurred on day 76. During pregnancy, ewe treatment had no effect on ewe live weight. However, average ewe body condition scores were higher in the shorn group than in the sham-shorn or cortisol groups (P < 0.05). Intramuscular injections of cortisol had a greater effect on ewe plasma cortisol concentrations than all other treatments (P < 0.05). Shearing produced a greater plasma cortisol response than isolation × 10 and sham-shearing (P < 0.05). Ewe plasma cortisol responses decreased during the 5 weeks of isolation and sham-shearing but cortisol injections produced a greater response during the fifth treatment than the first or ninth treatments (P < 0.05). Lambs born to shorn ewes were heavier and had a longer crown rump, forelimb and hind limb lengths than all other lambs (P < 0.05). In addition, lambs born to ewes in the cortisol treatment were lighter than lambs born to control, isolation × 2, isolation × 10 and shorn ewes (P < 0.05). The plasma cortisol concentrations observed for ewes injected with cortisol were far greater than those observed in all other groups, which is likely to explain the low birth weights of lambs born to ewes in that group. These results indicate that the mechanism by which mid-pregnancy shearing increases lamb birth weight is unlikely to be repeated stressors.


Identifying interactions in the time and frequency domains in local and global networks - A Granger Causality Approach.
Reverse-engineering approaches such as Bayesian network inference, ordinary differential equations (ODEs) and information theory are widely applied to deriving causal relationships among different elements such as genes, proteins, metabolites, neurons, brain areas and so on, based upon multi-dimensional spatial and temporal data. There are several well-established reverse-engineering approaches to explore causal relationships in a dynamic network, such as ordinary differential equations (ODE), Bayesian networks, information theory and Granger Causality. Here we focused on Granger causality both in the time and frequency domain and in local and global networks, and applied our approach to experimental data (genes and proteins). For a small gene network, Granger causality outperformed all the other three approaches mentioned above. A global protein network of 812 proteins was reconstructed, using a novel approach. The obtained results fitted well with known experimental findings and predicted many experimentally testable results. In addition to interactions in the time domain, interactions in the frequency domain were also recovered. The results on the proteomic data and gene data confirm that Granger causality is a simple and accurate approach to recover the network structure. Our approach is general and can be easily applied to other types of temporal data.


High-throughput elucidation of thrombus formation reveals sources of platelet function variability.
In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analyzed for conventional platelet phenotyping: i.e. hematologic parameters, platelet glycoprotein (GP) expression levels and activation markers (24 parameters). Furthermore, platelets were activated by ADP, CRP-XL or TRAP. Parallel samples were investigated for whole-blood thrombus formation (6 microspots, providing 48 parameters of adhesion, aggregation and activation). Microspots triggered platelet activation through GP Ib-V-IX, GPVI, CLEC-2 and integrins. For most thrombus parameters, inter-subject variation was 2-4 times higher than the intra-subject variation. Principal component analyses indicated coherence between the majority of parameters for the GPVI-dependent microspots, partly linked to hematologic parameters, and glycoprotein expression levels. Prediction models identified parameters per microspot that were linked to variation in agonist-induced αIIbβ3 activation and secretion. Common sequence variation of GP6 and FCER1G, associated with GPVI-induced αIIbβ3 activation and secretion, affected parameters of GPVI-and CLEC-2-dependent thrombus formation. Subsequent analysis of blood samples from patients with Glanzmann thrombasthenia or storage pool disease revealed thrombus signatures of aggregation-dependent parameters that were subject-dependent, but not linked to GPVI activity. Taken together, this high-throughput elucidation of thrombus formation revealed patterns of inter-subject differences in platelet function, which were partly related to GPVI-induced activation and common genetic variance linked to GPVI, but also included a distinct platelet aggregation component.


Analysis of the polycystins in aortic vascular smooth muscle cells.
The leading cause of death in autosomal dominant polycystic kidney disease (ADPKD) is cardiovascular. However, little is known about the pathogenesis of these manifestations. The present study was undertaken to characterize the ADPKD proteins, the polycystins, in vascular smooth muscle cells. It was demonstrated that the expression of polycystin-1 is developmentally regulated, whereas polycystin-2 has a more constant level of expression. A polycystin-1 subpopulation was immunoprecipitated by polycystin-2, indicating an in vivo interaction of these two proteins. Analysis with glycosidase and cell surface biotinylation indicates that some polycystin-1 products, but not polycystin-2, are located on the plasma membrane. Immunofluorescence showed that most of the polycystin-1 and polycystin-2 was cytoplasmic but that persistent polycystin-1 staining was located in proximity to the cell surface after a Triton-X extraction, whereas no clear surface localization of polycystin-2 was detected. Immuno-gold electron microscopy revealed that polycystin-1 was localized at the plasma membrane and sarcoplasmic reticulum, whereas polycystin-2 was mainly located in the sarcoplasmic reticulum. Both polycystins were found to be associated with dense plaques. These observations are consistent with an important role of the polycystins in the development, maintenance, and function of the myoelastic arterial organization and with the vascular phenotype associated with ADPKD.


Pediatric aleukemic leukemia cutis: report of 3 cases and review of the literature.
Leukemia cutis (LC) denotes a cutaneous infiltration of neoplastic myeloid cells or lymphoid blasts, which can present in the setting of acute myeloid leukemia, particularly in those cases with monocytic or myelomonocytic differentiation. Rarely, cutaneous involvement by a leukemic infiltrate can occur in the absence of bone marrow or peripheral blood involvement by acute leukemia; this then is referred to as aleukemic LC (ALC). Recognition of LC is important for further classification and early diagnosis of the disease, but the diagnosis is difficult in the absence of a systemic presentation of acute leukemia. Although the molecular and cytogenetic features of ALC are poorly characterized, some have shown specific molecular alterations in common with classic forms of acute leukemias. We present 3 cases of ALC in pediatric patients.


Effect of restraint stress duration on humoral immune response in albino rats: modulation by chlordiazepoxide.
We evaluated the effect of restraint stress (1 hr/day) for 6, 10, 14 and 21 days on antibody response against sheep RBC (SRBC) and modulation by chlordiazepoxide (CDP) pretreatment (10 mg/kg/day) in albino rats. Anti-SRBC titer was significantly decreased with increase in number of days of restraint stress exposure. CDP pretreatment significantly reversed the effects of 6, 10 and 14 (but not of 21) days of restraint stress. CDP treatment for 21 days per se suppressed immune response, but no additive effect was observed. CDP was not effective in chronic stress (i.e., 21 days of stress). Hence, the rationale behind benzodiazepines therapy in chronic stress needs to be evaluated.


Deranged hepatocyte intracellular Ca2+ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca2+ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca2+, and have provided evidence that altered Ca2+ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca2+ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca2+ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca2+ entry and SERCA2b, and activates Ca2+ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca2+ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca2+/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca2+ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca2+ transporters, channels, and binding proteins as targets for pharmacological intervention.


Body mass index history and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.
Obesity and increases in body weight in adults are considered to be among the most important risk factors for type 2 diabetes. The objective was to evaluate and compare the associations between weight changes during 2 different periods of adult life and the risk of type 2 diabetes and age at diagnosis. The study included 7720 men and 10 371 women from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study with information on weight history; 390 men and 303 women of these participants received a clinical diagnosis of type 2 diabetes during 7 y of follow-up. Multivariate Cox regression models were used to estimate the relative risk (RR) of weight changes between ages 25 and 40 y and ages 40 and 55 y. RR estimates in men and women were slightly higher for each unit of BMI gain between ages 25 and 40 y [men: 1.25 (95% CI: 1.21, 1.30); women: 1.24 (1.20, 1.27)] than between ages 40 and 55 y [men: 1.13 (1.10, 1.16); women: 1.11 (1.08, 1.14)]. Severe weight gain between ages 25 and 40 y was associated with a higher diabetes risk in men (1.5 times) and in women (4.3 times) than were stable weight in early adulthood and weight gain in later life, and it resulted in an average lower age at diabetes diagnosis in men (5 y) and in women (3 y). Weight gain in early adulthood is related to a higher risk and earlier onset of type 2 diabetes than is weight gain between 40 and 55 y of age.


Growth of bacteria on chitin, fungal cell walls and fungal biomass, and the effect of extracellular enzymes produced by these cultures on the antifungal activity of amphotericin B.
Vibrio alginolyticus, Streptomyces griseus, Arthrobacter G12, Bacillus sp. and Cytophaga sp. were grown on solid and liquid media containing soluble and insoluble carbon sources. Arthrobacter G12, Bacillus sp. and Cytophaga sp. grew well on media which contained fungal cell walls or fungal biomass as the main carbon source. All bacteria produced extracellular proteases and all bacteria except Arthrobacter G12 produced extracellular chitinases. Growth of Cytophaga sp. on colloidal chitin was paralleled by the accumulated chitinase activity in the culture filtrate, and growth of Cytophaga sp. and Arthrobacter G12 on cell walls of Geotrichum candidum and cell walls of Candida pseudotropicalis was paralleled by the accumulation of laminarinase activity in the culture filtrate, but little or no extracellular chitinase activity was observed in these cultures. Mycolases purified from the culture filtrates of Cytophaga sp. grown on colloidal chitin on cell walls of C. pseudotropicalis potentiated the antifungal activity of amphotericin B.


Movement disorders in adult surviving patients with maple syrup urine disease.
Maple syrup urine disease is a rare metabolic disorder caused by mutations in the branched-chain α-keto acid dehydrogenase complex gene. Patients generally present early in life with a toxic encephalopathy because of the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding ketoacids. Movement disorders in maple syrup urine disease have typically been described during decompensation episodes or at presentation in the context of a toxic encephalopathy, with complete resolution after appropriate dietary treatment. Movement disorders in patients surviving childhood are not well documented. We assessed 17 adult patients with maple syrup urine disease (mean age, 27.5 years) with a special focus on movement disorders. Twelve (70.6%) had a movement disorder on clinical examination, mainly tremor and dystonia or a combination of both. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 patients (64.7%), and a spastic-dystonic gait was observed in 6 patients (35.2%). In summary, movement disorders are common in treated adult patients with maple syrup urine disease, and careful neurological examination is advisable to identify those who may benefit from specific therapy. © 2011 Movement Disorder Society.


Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo.
Mesenchymal stem cells/multipotent stromal cells (MSCs) are promising therapeutics for a variety of conditions. However, after transplantation, cell retention remains extremely challenging. Given that many hypoxic signals are transitory and that the therapeutic administration of MSCs is typically into tissues that are normally hypoxic, we studied the effect of hypoxic preconditioning (HP) prior to new exposure to hypoxia. We show that preincubation for 2 days or more in 1% oxygen reduces serum deprivation-mediated cell death, as observed by higher cell numbers and lower incorporation of EthD-III and Annexin V. Consistently, HP-MSCs expressed significantly lower levels of cytochrome c and heme oxygenase 1 as compared to controls. Most importantly, HP-MSCs showed enhanced survival in vivo after intramuscular injection into immune deficient NOD/SCID-IL2Rgamma(-/-) mice. Interestingly, HP-MSCs consume glucose and secrete lactate at a slower rate than controls, possibly promoting cell survival, as glucose remains available to the cells for longer periods of time. In addition, we compared the metabolome of HP-MSCs to controls, before and after hypoxia and serum deprivation, and identified several possible mediators for HP-mediated cell survival. Overall, our findings suggest that preincubation of MSCs for 2 days or more in hypoxia induces metabolic changes that yield higher retention after transplantation.


A Fosmid Pool-Based Next Generation Sequencing Approach to Haplotype-Resolve Whole Genomes.
Haplotype resolution of human genomes is essential to describe and interpret genetic variation and its impact on biology and disease. Our approach to haplotyping relies on converting genomic DNA into a fosmid library, which represents the entire diploid genome as a collection of haploid DNA clones of ~40 kb in size. These can be partitioned into pools such that the probability that the same pool contains both parental haplotypes is reduced to ~1 %. This is the key principle of this method, allowing entire pools of fosmids to be massively parallel sequenced, yielding haploid sequence output. Here, we present a detailed protocol for fosmid pool-based next generation sequencing to haplotype-resolve whole genomes including the following steps: (1) generation of high molecular weight DNA fragments of ~40 kb in size from genomic DNA; (2) fosmid cloning and partitioning into 96-well plates; (3) barcoded sequencing library preparation from fosmid pools for next generation sequencing; and (4) computational analysis of fosmid sequences and assembly into contiguous haploid sequences.This method can be used in combination with, but also without, whole genome shotgun sequencing to extensively resolve heterozygous SNPs and structural variants within genomic regions, resulting in haploid contigs of several hundred kb up to several Mb. This method has a broad range of applications including population and ancestry genetics, the clinical interpretation of mutations in personal genomes, the analysis of cancer genomes and highly complex disease gene regions such as MHC. Moreover, haplotype-resolved genome sequencing allows description and interpretation of the diploid nature of genome biology, for example through the analysis of haploid gene forms and allele-specific phenomena. Application of this method has enabled the production of most of the molecular haplotype-resolved genomes reported to date.


Gesture Recognition Using Surface Electromyography and Deep Learning for Prostheses Hand: State-of-the-Art, Challenges, and Future.
Amputation of the upper limb brings heavy burden to amputees, reduces their quality of life, and limits their performance in activities of daily life. The realization of natural control for prosthetic hands is crucial to improving the quality of life of amputees. Surface electromyography (sEMG) signal is one of the most widely used biological signals for the prediction of upper limb motor intention, which is an essential element of the control systems of prosthetic hands. The conversion of sEMG signals into effective control signals often requires a lot of computational power and complex process. Existing commercial prosthetic hands can only provide natural control for very few active degrees of freedom. Deep learning (DL) has performed surprisingly well in the development of intelligent systems in recent years. The significant improvement of hardware equipment and the continuous emergence of large data sets of sEMG have also boosted the DL research in sEMG signal processing. DL can effectively improve the accuracy of sEMG pattern recognition and reduce the influence of interference factors. This paper analyzes the applicability and efficiency of DL in sEMG-based gesture recognition and reviews the key techniques of DL-based sEMG pattern recognition for the prosthetic hand, including signal acquisition, signal preprocessing, feature extraction, classification of patterns, post-processing, and performance evaluation. Finally, the current challenges and future prospects in clinical application of these techniques are outlined and discussed.