Allelic exclusion of TCR α-chains upon severe restriction of Vα repertoire.
Development of thymocytes through the positive selection checkpoint requires the rearrangement and expression of a suitable T cell receptor (TCR) α-chain that can pair with the already-expressed β-chain to make a TCR that is selectable. That is, it must have sufficient affinity for self MHC-peptide to induce the signals required for differentiation, but not too strong so as to induce cell death. Because both alleles of the α-chain continue to rearrange until a positively-selectable heterodimer is formed, thymocytes and T cells can in principle express dual α-chains. However, cell-surface expression of two TCRs is comparatively rare in mature T cells because of post-transcriptional regulatory mechanisms termed "phenotypic allelic exclusion". We produced mice transgenic for a rearranged β-chain and for two unrearranged α-chains on a genetic background where endogenous α-chains could not be rearranged. Both Vα3.2 and Vα2 containing α-chains were efficiently positively selected, to the extent that a population of dual α-chain-bearing cells was not distinguishable from single α-chain-expressors. Surprisingly, Vα3.2-expressing cells were much more frequent than the Vα2 transgene-expressing cells, even though this Vα3.2-Vβ5 combination can reconstitute a known selectable TCR. In accord with previous work on the Vα3 repertoire, T cells bearing Vα3.2 expressed from the rearranged minilocus were predominantly selected into the CD8+ T cell subpopulation. Because of the dominance of Vα3.2 expression over Vα2 expressed from the miniloci, the peripheral T cell population was predominantly CD8+ cells.


Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes.
Trypanosoma cruzi, the etiological agent of Chagas disease, is a protozoan parasite with a complex life cycle involving a triatomine insect and mammals. Throughout its life cycle, the T. cruzi parasite faces several alternating events of cell division and cell differentiation in which exponential and stationary growth phases play key biological roles. It is well accepted that arrest of the cell division in the epimastigote stage, both in the midgut of the triatomine insect and in vitro, is required for metacyclogenesis, and it has been previously shown that the parasites change the expression profile of several proteins when entering this quiescent stage. However, little is known about the metabolic changes that epimastigotes undergo before they develop into the metacyclic trypomastigote stage. We applied targeted metabolomics to measure the metabolic intermediates in the most relevant pathways for energy metabolism and oxidative imbalance in exponentially growing and stationary growth-arrested epimastigote parasites. We show for the first time that T. cruzi epimastigotes transitioning from the exponential to the stationary phase exhibit a finely tuned adaptive metabolic mechanism that enables switching from glucose to amino acid consumption, which is more abundant in the stationary phase. This metabolic plasticity appears to be crucial for survival of the T. cruzi parasite in the myriad different environmental conditions to which it is exposed during its life cycle.


2-Hydroxy-4-methoxybenzaldehyde from Hemidesmus indicus is antagonistic to Staphylococcus epidermidis biofilm formation.
Staphylococcus epidermidis (SE) is an opportunistic nosocomial pathogen that accounts for recalcitrant device-related infections worldwide. Owing to the growing interest in plants and their secondary metabolites targeting bacterial adhesion, this study was intended to uncover the anti-biofilm potential of Hemidesmus indicus and its major constituent 2-hydroxy-4-methoxybenzaldehyde (HMB) against SE. The minimum biofilm inhibitory concentration (MBIC) of H. indicus root extract and HMB were found to be 500 and 250 µg ml-1, respectively. The results of time-dependent biofilm inhibition and mature biofilm disruption assays confirmed that HMB targets initial cell adhesion. Furthermore, interference by HMB in the expression of adhesin genes (icaA, aap and bhp) and biofilm components was associated with an increased susceptibility of SE to oxidative stress and antibiotics. To conclude, this study reports for the first time HMB as a potential drug against SE biofilms.


Using transitional implants during the healing phase of implant reconstruction.
The use of dental implants to reconstruct the fully and partially edentulous jaw has been well-documented in the literature. Simplification of the healing phase with transitional implants is becoming a routine step in the management of the integration period for the patient undergoing implant reconstruction. Restoration and maintenance of vertical dimension with transitional implants in conjunction with implant surgical therapy is an effective method to provide the patient with an immediate and comfortable transitional appliance. This approach facilitates the uneventful reconstruction with the definitive prosthesis.


The Small G Protein AtRAN1 Regulates Vegetative Growth and Stress Tolerance in Arabidopsis thaliana.
The evolutionarily conserved small G-protein Ran plays important role in nuclear translocation of proteins, cell cycle regulation, and nuclear envelope maintenance in mammalian cells and yeast. Arabidopsis Ran proteins are encoded by a family of four genes and are highly conserved at the protein level. However, their biological functions are poorly understood. We report here that AtRAN1 plays an important role in vegetative growth and the molecular improvement of stress tolerance in Arabidopsis. AtRAN1 overexpression promoted vegetative growth and enhanced abiotic tolerance, while the atran1 atran3 double mutant showed higher freezing sensitivity than WT. The AtRAN1 gene is ubiquitously expressed in plants, and the expression levels are higher in the buds, flowers and siliques. Subcellular localization results showed that AtRAN1 is mainly localized in the nucleus, with some present in the cytoplasm. AtRAN1 could maintain cell division and cell cycle progression and promote the formation of an intact nuclear envelope, especially under freezing conditions.


Bayesian Structure Learning in Multi-layered Genomic Networks.
Integrative network modeling of data arising from multiple genomic platforms provides insight into the holistic picture of the interactive system, as well as the flow of information across many disease domains including cancer. The basic data structure consists of a sequence of hierarchically ordered datasets for each individual subject, which facilitates integration of diverse inputs, such as genomic, transcriptomic, and proteomic data. A primary analytical task in such contexts is to model the layered architecture of networks where the vertices can be naturally partitioned into ordered layers, dictated by multiple platforms, and exhibit both undirected and directed relationships. We propose a multi-layered Gaussian graphical model (mlGGM) to investigate conditional independence structures in such multi-level genomic networks in human cancers. We implement a Bayesian node-wise selection (BANS) approach based on variable selection techniques that coherently accounts for the multiple types of dependencies in mlGGM; this flexible strategy exploits edge-specific prior knowledge and selects sparse and interpretable models. Through simulated data generated under various scenarios, we demonstrate that BANS outperforms other existing multivariate regression-based methodologies. Our integrative genomic network analysis for key signaling pathways across multiple cancer types highlights commonalities and differences of p53 integrative networks and epigenetic effects of BRCA2 on p53 and its interaction with T68 phosphorylated CHK2, that may have translational utilities of finding biomarkers and therapeutic targets.


Virological and Serological Characterisation of SARS-CoV-2 Infections Diagnosed After mRNA BNT162b2 Vaccination Between December 2020 and March 2021.
Vaccines for coronavirus disease 2019 (COVID-19) are proving to be very effective in preventing severe illness; however, although rare, post-vaccine infections have been reported. The present study focuses on virological and serological features of 94 infections that occurred in Lazio Region (Central Italy) between 27 December 2020, and 30 March 2021, after one or two doses of mRNA BNT162b2 vaccine. We evaluated clinical features, virological (viral load; viral infectiousness; genomic characterisation), and serological (anti-nucleoprotein Ig; anti-Spike RBD IgG; neutralising antibodies, nAb) characteristics of 94 post-vaccine infections at the time of diagnosis. Nasopharyngeal swabs (NPSs) and serum samples were collected in the framework of the surveillance activities on SARS-CoV-2 variants established in Lazio Region (Central Italy) and analysed at the National Institute for Infectious Diseases "L. Spallanzani" in Rome. The majority (92.6%) of the post-vaccine infections showed pauci/asymptomatic or mild clinical course, with symptoms and hospitalisation rate significantly less frequent in patients infected after full vaccination course as compared to patients who received a single dose vaccine. Although differences were not statistically significant, viral loads and isolation rates were lower in NPSs from patients infected after receiving two vaccine doses as compared to patients with one dose. Most cases (84%) had nAb in serum at the time of infection diagnosis, which is a sub-group of vaccinees, were found similarly able to neutralise Alpha and Gamma variants. Asymptomatic individuals showed higher nAb titres as compared to symptomatic cases (median titre: 1:120 vs. 1:40, respectively). Finally, the proportion of post-vaccine infections attributed either to Alpha and Gamma variants was similar to the proportion observed in the contemporary unvaccinated population in the Lazio region, and mutational analysis did not reveal enrichment of a defined set of Spike protein substitutions depending on the vaccination status. Our study conducted using real-life data, emphasised the importance of monitoring vaccine breakthrough infections, through the characterisation of virological, immunological, and clinical features associated with these events, in order to tune prevention measures in the next phase of the COVID-19 pandemic.


[Immunosuppression induced by measles virus in adult patients is not related to CD4+ CD25+ regulatory T cell induction].
To investigate of the relationship of the immunosuppression induced by Measles virus in adult patients and CD4+ CD25+ regulatory T cell. Thirty-four patients with measles and 27 healthy control subjects were included in this study. The whole blood was collected and CD4+ CD25+ cell and FoxP3+ cell were analyzed by flow cytometry, and CD4+ CD25- and CD4+ CD25+ T lymphocytes were isolated from PBMCs of patients with measles or healthy donors, CD4+ CD25- T cells were cultured in absence or presence of anti-CD3, or BCG, or live attenuated MV. The cell culture supernatant was collected after 72 hours and the concentration of IFN-gamma and IL-10 was determined. Compared to healthy donors, we observed a reduction of the number of white blood cells and lymphocytes in patients with measles, but there was not significantly different in the frequency of CD4+ CD25+ T cells and CD4+ CD25high T cells within the total CD4+ population in the blood. Treg from both measles patients and healthy controls significantly inhibited IFN-gamma production by CD4+ CD25- T cells in response to anti-CD3 stimulation. Induction and expansion of Treg may not represent a mechanism involved in the establishment of immune suppression by MV.


The neurobehavioural evaluation in schizophrenics: a comparative study.
The simple reaction time task assesses the ability of the subject to respond to an external cue and to retrieve a reward. The reaction time provides an indirect index of the processing capability of the central nervous system and a simple means to the determined sensory and the motor performances, which is a neurobehavioural evaluation. A general slowness in the latency in the reaction time tasks and a disengagement deficit in the visual and the hearing oriented tasks were seen in schizophrenics. In order to clarify the feature of the attention disorders in schizophrenia, a simple reaction time task was given to schizophrenics. Schizophrenics (34 males and 20 females, n=54) and healthy controls (40 males and 21 females, n=61) with a mean age of 35±7, who were individually matched for gender and age, were included in the study, by using a response analyser to evaluate the reaction time. The performances were expressed in mean ± standard deviation of the reaction time by using the unpaired 't' test. The schizophrenic patients performed poorer than the healthy controls, which indicated a difficulty in sustaining attention and this was statistically very highly significant (p<0.000). The results suggested that the schizophrenics showed inattentiveness in the clinical settings and an emotional disturbance in interpersonal situations. The increased reaction time as compared to that in healthy controls, might be due to the impairment of the psychomotor poverty, disorganization and reality distortion which were associated with the deficits in the cortical neurological functions, such as planning, coordination and sequencing of the motor acts, which showed a greater involvement of the frontal lobe and temporal lobe dysfunction.


[From Amiens to Quebec: the first milestones of an on-going adventure].
The first two international conferences on local and regional health programmes held in Amiens and Quebec have paved the road for a new public health paradigm. The conferences have served to share experiences from the field to re-think practice and create bridges between health promotion, prevention, care and integration at both the action and decision levels, and amongst diverse actors from the field. The challenges have been put forth, in Amiens in 2001 and in Quebec three years later. The next step is to pursue and enrich these exchanges at the international level reinforcing the Francophone position by capitalising on approaches and tools, and mobilising new partners. The next rendezvous for this on-going adventure is set for the third conference.


Material behavior of resin composites with and without fibers after extended water storage.
The objective of this study was to determine the long-term water sorption, solubility and hygroscopic expansion of resin composites with and without incorporated short fibers. Three resin composites incorporating fibers were examined: everX Posterior (EVX), NovoPro Universal (NPU) and NovoPro Flow (NPF). Four Particulate filled composites were used as controls: Filtek bulk Fill (FBF), Filtek one bulkfill (FBO), Filtek Supreme XTE (XTE), and Filtek Supreme Flow (XTEF). For sorption and solubility measurements, specimens were immersed in water for140 days, weighed at intervals, then dried for a further 42 days at 37±1°C. Laser micrometer measured diametral expansion. XTEF exhibited the highest sorption. The solubility range was between -1.4 to 4.1 μg/mm; XTEF had the highest solubility, with EVX demonstrating negative solubility. Hygroscopic expansion ranged between 1.4% for hydroxyapatite fiber reinforced composite (NPU) and 2.2% for E-glass fiber reinforced composite (EVX). A nano-fiber containing composite (NPU) had the most favorable outcomes compared to a range of composites.


Is HMGB1 a new indirect marker for revealing fibrosis in chronic hepatitis and a new therapeutic target in treatment?
In chronic hepatitis B virus (HBV) infection, inflammation-associated cytokines including proinflammatory cytokines are involved in the development and progression of liver fibrosis. The liver is a source of many cytokines that may influence liver function. High-mobility group box 1 (HMGB1) was identified as an inflammatory cytokine. HMGB1 is present in nuclei of all mammalian cells and is released both through active secretion from various cells and by passive release from necrotic cells. Here we explore the relationship between HMGB1 plasma levels and liver fibrosis. HMGB1 serum levels, HBV-DNA, and ALT values were significantly higher in patients with chronic HBV than in controls. In addition, HMGB1 serum levels were significantly higher in patients with low fibrosis (fibrosis score 1-2) compared to those with high fibrosis (fibrosis score 3-4). In the present study, we have shown that HMGB1 is a noninvasive, repeatable, and convenient marker for distinguishing advanced fibrosis from low fibrosis in chronic HBV patients. We believe that the inhibition of HMGB1 may reduce inflammation, apoptosis, and fibrosis, and may stop the progression of chronic liver disease. Furthermore, we are of the opinion that fibrotic progression in chronic liver patients may be prevented by the inhibition of HMGB1, and that this substance can be a new means of following chronic HBV treatment.


Hospitalization rates among economic immigrants to Canada.
Economic immigrants generally, and economic class principal applicants (ECPAs) specifically, tend to have better health than other immigrants. However, health outcomes vary among subcategories within this group, especially by sex. This study examines hospitalization rates among ECPAs aged 25 to 74 who arrived in Canada between 1980 and 2006 as skilled workers, business immigrants, or live-in caregivers. The analysis used two linked databases to estimate age-standardized hospitalization rates (ASHRs) overall and for leading causes by sex. ASHRs of ECPA subcategories were compared with each other and with those of the Canadian-born population. Logistic regression was used to derive odds ratios for hospitalization among ECPAs, by sex. Male and female ECPAs aged 25 to 74 had significantly lower all-cause ASHRs than did the Canadian-born population in the same age range. This pattern prevailed for each ECPA subcategory and for each disease examined. Compared with skilled workers, business immigrants had lower odds of hospitalization; live-in caregivers who arrived after 1992 had higher odds. Adjustment for education, official language proficiency, and world region reduced the strength of or eliminated these associations. Compared with the Canadian-born population, ECPAs generally had low hospitalization rates. Differences were apparent among ECPA subcategories.


Cytoplasmic biotin-like activity interferes with immunohistochemical analysis of thyroid lesions: a comparison of antigen retrieval methods.
Cytoplasmic biotin-like activity was identified in formalin-fixed and paraffin-embedded human thyroid lesions by immunostaining for biotin by use of the peroxidase-antiperoxidase method or by peroxidase-labeled streptavidin alone. The reactivity of cytoplasmic biotin-like activity was markedly enhanced both by pretreatment with trypsin and after heating by autoclaving. Of 208 thyroid lesions, 93 showed positive immunostaining for biotin with use of trypsin pretreatment. The positive incidence of cases and positive cell ratio were highest in papillary carcinoma, followed by follicular carcinoma but lowest in the lethal types of thyroid carcinoma: anaplastic carcinoma, squamous cell carcinoma and poorly differentiated insular carcinoma. We conclude that cytoplasmic biotin-like activity in the common thyroid neoplasms should be considered as an interfering factor for immunostaining with avidin-biotin combined with selected antigen retrieval methods and with in situ hybridization with biotinylated probes.


4-year clinical performance and survival analysis of Class I and II compomer restorations in permanent teeth.
To evaluate the 4-year clinical performance of the compomer Hytac in Class I and II cavities of permanent posterior teeth. 53 compomer restorations were placed using the self-conditioning adhesive Hytac OSB (total bonding) without additional phosphoric acid-etching according to manufacturer's instructions. Restorations were rated (modified USPHS criteria) at baseline, after 6, 12, 18, 36 and 48 months in relation to tooth type (molar, premolar), size and class of cavities, isolation type (rubber dam, cotton rolls) and use of a calcium hydroxide liner. After 4 years, 39 restorations (73.6%) were available for examination. Statistical analysis was performed using Kaplan-Meier survival analysis with the logrank test and Fisher's exact test for the failure analysis. After 4 years, the success rate was 84.6%, six restorations failed (15.4%). The average annual failure rate was therefore 3.85%. Loss of marginal integrity was the main cause of restoration failure. The probability that a restoration would remain clinically acceptable after 4 years was calculated to be 89% (Kaplan-Meier). No significant performance differences could be found between any of the restoration groups.


Immunoglobulin-like transcripts as risk genes for autoimmunity.
Risk genes for multiple sclerosis (MS) are localized in the gene regions 6p21-11 and 19q13, the latter harboring the genes of the immunoglobulin-like transcripts (ILTs). ILTs are a family of activating and inhibitory receptors expressed on antigen-presenting cells (APCs) as well as on natural killer (NK) and T cells. Because of the inhibitory function of ILT2 and ILT4 and their binding to human leukocyte antigen (HLA)-G, they play a role in immune tolerance and may be important in pathogenesis of autoimmunity. ILT6 shows presence-absence variability and is produced by macrophages in a soluble form. ILT6 deletion is associated with MS. Furthermore, ILT6 activates T cell proliferation and is therefore a candidate gene for autoimmune disorders.


Intracranial infantile myofibromatosis with intraparenchymal involvement.
Infantile myofibromatosis is the most common fibrous disorder of infancy and early childhood. Intracranial involvement is rare, with the majority of lesions being localized to the skull or dura with variable intracranial extension. We present the case of a 19-month-old girl with infantile myofibromatosis and an incidentally discovered, enlarging, calcified, posterior fossa mass. The patient underwent suboccipital craniotomy and resection of the lesion. This is the first report of the surgical removal of an intraparenchymal infantile myofibroma.


Job dissatisfaction in lecturers in School of Medical Sciences Universiti Sains Malaysia and Faculty of Medicine Universiti Kebangsaan Malaysia.
Job dissatisfaction in doctors and teachers is known to have direct consequences on the quality of service and teaching for patients and students respectively. A cross-sectional study to assess dissatisfaction in lecturers of School of Medical Sciences, Universiti Sains Malaysia (USM) and Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM) was undertaken between August 2001 and May 2002. The original English version of the Job Content Questionnaire (CQ) version 1.7 (revised 1997) by Robert Karasek was self-administered to 73 (response rate 58.4%) and 80 (response rate 41.7%) lecturers in the medical faculties of USM and UKM, respectively. The prevalence of job dissatisfaction in USM and UKM lecturers were 42.6% and 42.9%, respectively; the difference was not significant (p>0.05). Risk factors of job dissatisfaction in USM lecturers were decision authority (p<0.001) and psychological job demand (p<0.001). Significant risk factors of job dissatisfaction in UKM lecturers were skill discretion (p<0.01) and psychological job demand (p<0.001). We conclude that psychological job demand was a risk factor of job dissatisfaction in both USM and UKM lecturers; in USM, decision authority was protective, while in UKM, skill discretion was protective against job dissatisfaction.


Lipoperoxidation as a measure of free radical injury in otitis media.
Free radical damage, as evidenced by lipoperoxidation, has previously been demonstrated to contribute to the inflammatory changes associated with acute otitis media. The present study was undertaken to evaluate whether lipoperoxidation continues to be present for a period of time after middle ear infection. Eighty-two 300- to 400-g guinea pigs were injected with Streptococcus pneumoniae in the left ear and sterile saline in the right ear as a control. Animals were examined and sacrificed on day 5, 10, 20, or 30; middle ear mucosa was harvested and assayed for lipid hydroperoxide content. A statistically significant increase in lipoperoxidation was seen at each time point studied, compared with controls. Lipoperoxidation was highest at days 5 and 10; a significant decrease was seen at days 20 and 30. Histologic sections of middle ear mucosa of two animals per group were prepared and evaluated for inflammation. These results demonstrate that lipoperoxidation may contribute to middle ear inflammation for a significant period of time after acute infection; the findings are discussed in light of other work on the role of free radicals in otitis media.


Temperature dependence of near-infrared spectra of whole blood.
The temperature dependence (30 to 40 degrees C) of near-infrared spectra (500 to 1100 nm) of whole human blood, including red blood cells with intact physiological function, is investigated. Previous studies have focused on hemoglobin solutions, but the operation of red blood cells is critically dependent on intact cell membranes to perform normal oxygen transport and other physiological functions. Thus measurements of whole blood are more directly related to changes that occur in vivo. In addition to the response of hemoglobin to temperature in the spectra, a temperature response from water in the plasma is also detected. The temperature response of the water absorption at 960 nm is approximately ten times smaller than the temperature response of the oxyhemoglobin component in the blood at 610 nm. However, it is the most significant temperature effect between 800 and 1000 nm. This work will aid the precision and understanding of full spectrum near-infrared measurements on blood.


[Effect of isolation of the mediobasal hypothalamus on the predatory aggressiveness of rats].
A study was made of the influence of isolation of the medio-basal hypothalamus area on the predatory aggression of albino male rats, which was measured by the test of mouse-killing. In three weeks after the operation the aggressiveness of rats increased eightfold. Partial isolations--anterior, long-posterior and posterior--did not change the killing aggression of the rats. Extension of dimensions of complete isolation up to the lateral hypothalamic area did not lead to the appearance of "mice killers" among the experimental rats. A conclusion has been drawn that the medio-basal hypothalamus has an inhibitory effect on the predatory aggression, which is achieved in multiple ways and is directed at the lateral hypothalamus.


131I-asialo-alpha 1-acid glycoprotein. Investigation of its use for liver function tests; metabolism in the rat.
On intravenous injection into rats, 131I-asialo-alpha 1-acid glycoprotein was rapidly removed from the circulation. Five minutes after injection only a few per cent of the injected dose remained in the plasma and 75 per cent was found to be in the liver, where it could be localized in the hepatocytes. Fifteen minutes after injection, however, the 131I reappeared in the plasma after the labeled protein had been metabolized by the liver. One hour after injection less than 5 per cent of the injected dose remained in the liver. Studies with this material in a series of rats using a gammacamera showed the reproducibility of the the time-activity curves of the liver. In contrast, the unmodified radioactive alpha 1-acid glycoprotein disappeared from the blood at a much slower rate. The disappearance curve of the unmodified alpha1-acid glycoprotein could be fitted with the sum of two exponential curves with half-times of 2.88 H. and 27.3 H., respectively. The 131I-alpha1-acid glycoprotein did not accumulate in any tissue except the kidneys and some of the radioactivity was excreted in the urine. The possible application of 131I-asialo-alpha1-acid glycoprotein and the comparison with other radiopharmaceuticals for liver studies in nuclear medicine are discussed.


Platelet factor 3 in normal subjects and patients with renal failure.
Two tests were used to differentiate abnormalities in release of platelet factor 3 (PF3) from quantitative deficiencies of this factor in normal subjects and in patients with renal failure. The first test was an assay which determined availability of PF3 (PF3-A time) and involved the use of a mixture of patient's platelet-rich plasma (PRP) and normal platelet-poor plasma (PPP) in a fixed ratio (1:8). The second test was similar but used "frozen and thawed" platelets to obtain a quantitative estimate of PF3 (PF3-F time). An abnormal PF3-A time was found in approximately three-quarters of 55 patients with renal insufficiency; 43 of these had chronic and 12 had acute renal failure. This abnormality was present both in patients with and without hemorrhagic manifestations, although it was slightly more common in bleeders. The PF3-F test was abnormal in approximately one-third of the bleeding patients and one-quarter of the non-bleeders. The PF3-A time returned to normal or was significantly shortened 24-48 hr after peritoneal or hemodialysis. Studies on patients who were not dialyzed showed no statistically significant correlations between the PF3-A time and either the serum urea nitrogen, creatinine, calcium, or phosphorus. Furthermore, the PF3-A time was not affected by guanidinosuccinic or guanidinoacetic acids. We therefore conclude that the demonstrable platelet abnormality in patients with uremia is produced by an unknown dialyzable material. The mean plasma clot retraction of uremic patients was also significantly different from the mean plasma clot retraction or normal controls. However, unlike the PF3-A time, the abnormality of plasma clot retraction was not immediately affected by dialysis. Correction of plasma clot retraction did occur after repeated dialyses.


Monthly Trends in the Life Events Reported in the Prior Year and First Year of the COVID-19 Pandemic in New Zealand.
The current study examines changes in the economic, social, and well-being life events that women and men reported during the first 7 months of the COVID-19 pandemic. Analyses compared monthly averages in cross-sectional national probability data from two annual waves of the New Zealand Attitudes and Values Study collected between October 2018-September 2019 (N = 17,924), and October 2019-September 2020 (N = 41,653), which included the first 7 months of the pandemic (Mar-Sep 2020). Results indicated that people (particularly women) reported increased job loss in the months following an initial COVID-19 lockdown relative to the same months the year earlier. Women also experienced an increase in family troubles when restrictions eased and reported increased negative lifestyle changes that persisted throughout the first 7 months of the pandemic. The proportion of people experiencing many other life events (e.g., mental health, financial concerns) in New Zealand did not differ reliably from the pre-pandemic monthly baseline. These results highlight resilience to many potential negative life events within the first 7 months of the COVID-19 pandemic. However, the pandemic did not affect everyone equally, and the burden of increased negative events appears more heavily borne by women. As the pandemic continues more than 18 months from initial community transmission of COVID-19, our findings provide important insight into the impact of the pandemic on potential negative life events, especially among women, that may have critical consequences for mental health, gender equality, and social well-being over time.


Assessment of valvular heart disease by Doppler echocardiography.
Doppler echocardiography provides direct hemodynamic data that are often complementary to those demonstrated by M-mode and two-dimensional echocardiographic imaging. This relatively new noninvasive technique has a number of important uses in patients with valvular heart disease. In both adults and children, Doppler measures of peak flow velocity through a stenotic valve allow accurate prediction of the pressure gradient across the valve, and the technique has particular promise for screening patients with suspected aortic or pulmonic stenosis. In patients with mitral stenosis but parasternal short-axis images of limited quality, Doppler velocity measures can provide novel data about the pressure gradient and mitral orifice area. Doppler techniques can also provide direct evidence for or against the presence of valvular regurgitation, and several approaches allow clinically useful estimation of the extent of aortic, mitral, or tricuspid regurgitation. In patients with known disease of one cardiac valve, Doppler is accurate for evaluating the integrity of a second valve. Finally, Doppler techniques have great promise for defining the nature, and perhaps the severity, of suspected prosthetic valve malfunction. Hence, we believe that Doppler echocardiography should become a routine part of the noninvasive evaluation of patients with known or suspected valvular heart disease.


LOXL null mice demonstrate selective dentate structural changes but maintain dentate granule cell and CA1 pyramidal cell potentiation in the hippocampus.
Lysyl oxidase-like protein (LOXL), part of the lysyl oxidase copper-dependent amine oxidase family, is expressed in the extracellular matrix and in the nucleus. It likely plays a role in cross-linking collagen and elastin, possibly modulating cellular functions. Immunohistochemical studies show the presence of LOXL in the pyramidal cell layer of the hippocampus; and in this study, we report that cells in the granule cell layer have significantly smaller somas in LOXL -/- compared to LOXL +/+ mice. In addition we tested the hypothesis that these structural alterations in the dentate granule layer were associated with synaptic efficacy and thus muted long-term potentiation in mice lacking the protein. Electrical recordings were obtained in 300-mum hippocampal slices in dentate and CA1 pyramidal cell layers in age-matched wild type and LOXL null mice. Potentiation in the CA1 cell layer of 10 LOXL -/- and 8 LOXL +/+ mice was 191.0+/-9.3% and 181.6+/-9.1%, respectively (mean+/-S.E.M.). Dentate potentiation was 120.8+/-7.0% and 121.0+/-3.4% in 11 LOXL -/- and 11 LOXL +/+ mice, respectively. No phenotypic difference in potentiation of population spike amplitude (or in EPSP slope) in either layer was observed. Thus, contrary to expectation, structural changes in the hippocampus of LOXL -/- mice did not affect synaptic remodeling in a manner that impaired the establishment of LTP.


Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis.
The current meta-analytic study explored the relation between ACE gene insertion/deletion (I/D), and the risk of EH by reviewing relevant trials so as to determine the association between Angiotensin Converting Enzyme (ACE) gene polymorphism and essential hypertension (EH) susceptibility. Relevant studies published before May 2019 were collected from the PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP databases. Fifty-seven studies involving a total of 32,862 patients were included. These studies found that ACE gene D allele was associated with higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model, and that Asian population with ACE gene D allele showed a higher EH susceptibility in all these models. Moreover, ACE gene D allele was found closely related to a higher EH susceptibility in the subgroups of HWE, NO HWE, Caucasian population, and Mixed population, with the majority being males in allelic model, homozygote model, and regressive model and the majority being females in allelic model. ACE gene D allele is associated with an overall higher EH susceptibility, which is confirmed in the subgroup analysis of Asian population, HWE, NO HWE, Caucasian population, and Mixed population.


Prevention and control of methicillin-resistant Staphylococcus aureus infections.
This article reviews many recent publications relevant to the prevention and control of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. Higher risk-adjusted costs and mortality have been found for MRSA infections than for methicillin-susceptible S. aureus infections confirming their epidemiologic importance. Staphylococcal cassette chromosome mec, the genetic basis for MRSA, does not develop in methicillin-susceptible S. aureus exposed to antimicrobials. Instead virtually all patients acquire MRSA via spread. Nevertheless, antibiotic therapy provides a selective advantage for such spread, especially within healthcare settings where antimicrobial therapy is most frequent. Several studies have suggested better control of MRSA through antibiotic control, but far more studies have reported control using surveillance cultures and contact precautions for preventing spread (rather than just using standard precautions). More rapid detection of MRSA (within 6 h) has been reported using polymerase chain reaction, but studies using this method to reduce spread have not yet been published. A structured survey of research methods used regarding MRSA control noted that many studies had methodologic shortcomings (for example, none was a randomized trial), but nevertheless concluded that active detection and isolation work should be used. A Society for Healthcare Epidemiology of America guideline emphasized the same approach noting that scores of studies on multiple continents had reported success with this approach, with best results in several northern-European countries where all facilities used it routinely. Improved MRSA control is possible by detecting and isolating colonized patients.


Time-resolved photoluminescence characteristics of subnanometer ZnO clusters confined in the micropores of zeolites.
Subnanometric ZnO clusters confined in different micropore zeolites are studied by steady-state and nanosecond time-resolved photoluminescence (PL) spectroscopy. The microsecond-scale lifetime is observed at room temperature for ZnO clusters confined in zeolites, which is significantly different from that of macrocrystalline ZnO on the external surface of zeolites. The dependence of luminescence lifetime on the amount of ZnO in zeolites indicates that the electron-phonon interactions between the ZnO clusters and the zeolite host significantly affect the dynamic relaxation process of ZnO clusters. The long lifetime luminescence of ZnO clusters can be achieved by weakening the coupling of electronic transition to zeolites host phonons. The similar long-lived luminescence is obtained when dispersing ZnO clusters into the porous SiO2. It is suggested that encapsulating the semiconductor cluster in the porous support is a possible way to inhibit or to retard the electron-hole recombination.


Cardioprotective effect of K-7259, a novel dilazep derivative, against ischemia-reperfusion damage in isolated, working rat hearts.
Global ischemia (15 min) followed by reperfusion (10, 20 or 30 min) was performed in isolated, working rat hearts. Ischemia depressed mechanical function, which was not restored by reperfusion of 20 min. Preischemic administration of K-7259 (N,N'-bis[4-(3,4,5-trimethoxyphenyl)butyl]homopiperazine dihydrochloride) (1, 5 or 10 microM) decreased the function before ischemia, but it attenuated the ischemia-induced dysfunction during reperfusion (20 min). Postischemic administration of K-7259 (10 microM) or dilazep (20 microM) also attenuated the ischemia-induced dysfunction during reperfusion (30 min). Ischemia-reperfusion (10 min) increased the tissue malondialdehyde level, and postischemic administration of K-7259 (10 microM) or dilazep (20 microM) attenuated the malondialdehyde accumulation. K-7259 has a cardioprotective effect when given either before or after ischemia.


Engineered yeasts and lignocellulosic biomaterials: shaping a new dimension for biorefinery and global bioeconomy.
The next milestone of synthetic biology research relies on the development of customized microbes for specific industrial purposes. Metabolic pathways of an organism, for example, depict its chemical repertoire and its genetic makeup. If genes controlling such pathways can be identified, scientists can decide to enhance or rewrite them for different purposes depending on the organism and the desired metabolites. The lignocellulosic biorefinery has achieved good progress over the past few years with potential impact on global bioeconomy. This principle aims to produce different bio-based products like biochemical(s) or biofuel(s) from plant biomass under microbial actions. Meanwhile, yeasts have proven very useful for different biotechnological applications. Hence, their potentials in genetic/metabolic engineering can be fully explored for lignocellulosic biorefineries. For instance, the secretion of enzymes above the natural limit (aided by genetic engineering) would speed-up the down-line processes in lignocellulosic biorefineries and the cost. Thus, the next milestone would greatly require the development of synthetic yeasts with much more efficient metabolic capacities to achieve basic requirements for particular biorefinery. This review gave comprehensive overview of lignocellulosic biomaterials and their importance in bioeconomy. Many researchers have demonstrated the engineering of several ligninolytic enzymes in heterologous yeast hosts. However, there are still many factors needing to be well understood like the secretion time, titter value, thermal stability, pH tolerance, and reactivity of the recombinant enzymes. Here, we give a detailed account of the potentials of engineered yeasts being discussed, as well as the constraints associated with their development and applications.


Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis.
We performed a systematic review and meta-analysis on the relation between fluoride exposure and skeletal fluorosis (SF) using a novel statistical methodology for dose-response modeling. Skeletal fluorosis, a major health issue that is endemic in some regions, affects millions of people worldwide. However, data regarding the dose-response relation between fluoride exposure and SF are limited and outdated. We included twenty-three studies in the meta-analysis. When comparing the highest versus the lowest fluoride category, the summary risk ratio (RR) for SF prevalence was 2.05 (95% CI 1.60; 2.64), with a value of 2.73 (95% CI 1.92; 3.90) for drinking water and 1.40 (95% CI 0.90; 2.17) for urinary fluoride. The RR by the risk of bias (RoB) was 2.37 (95% CI 1.56; 3.58) and 1.78 (95% CI 1.34; 2.36) for moderate and high RoB studies, respectively. The dose-response curve based on a one-stage cubic spline regression model showed an almost linear positive relation between exposure and SF occurrence starting from relatively low concentrations up to 5 mg/L and 2.5 mg/L, respectively, for water and urinary fluoride, with no substantial increase above this threshold. The RR for developing moderate-severe forms increases at 5.00 mg/L and 2.5 mg/L of water and urinary fluoride, respectively. Better-quality studies are needed to confirm these results, but greater attention should be given to water fluoride levels to prevent SF, in addition to the other potential adverse effects of fluoride exposure.


International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated new guidelines. Since the levels of evidence for all items addressed in these guidelines are low, being 4 or 5, we still have to designate them "consensus", rather than "evidence-based", guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required.


Heartburn. The role of radiology.
There is currently controversy as to the importance of the radiologic demonstration of a hiatal hernia, reflux, or both as the explanation of heartburn. It is clear, however, that clinical-radiologic correlation requires additional observations such as the straightness of the potential path for reflux, the presence of a contractile esophagogastric region, the degree of extrinsic compression of the cuff of the stomach within the hiatus, the size of the hernia, and the peristaltic activity of the body of the esophagus. Vigorous or water-swallowing maneuvers to demonstrate reflux are unreliable in individual cases. Of importance is the concept that the so-called patulous cardia, or effaced abdominal esophagus or widened or absent "submerged segment," is a variety of sliding hiatal hernia that is often neglected radiologically but may be of considerable clinical significance.


The canonical ensemble via symplectic integrators using Nosé and Nosé-Poincaré chains.
Simulations that sample from the canonical ensemble can be generated by the addition of a single degree of freedom, provided that the system is ergodic, as described by Nosé with subsequent modifications by Hoover to allow sampling in real time. Nosé-Hoover dynamics is not ergodic for small or stiff systems and the addition of auxiliary thermostats is needed to overcome this deficiency. Nosé-Hoover dynamics, like its derivatives, does not have a Hamiltonian structure, precluding the use of symplectic integrators which are noted for their long term stability and structure preservation. As an alternative to Nosé-Hoover, the Hamiltonian Nosé-Poincaré method was proposed by Bond, Laird, and Leimkuhler [J. Comput. Phys. 151, 114 (1999)], but the straightforward addition of thermostatting chains does not sample from the canonical ensemble. In this paper a method is proposed whereby additional thermostats can be applied to a Hamiltonian system while retaining sampling from the canonical ensemble. This technique has been used to construct thermostatting chains for the Nosé and Nosé-Poincaré methods.


Correction: IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
[This corrects the article DOI: 10.1371/journal.pone.0144654.].


Conjunctival lymphangioma: a case report and brief review of the literature.
Background. Lymphangioma is a rare venolymphatic lesion, characterized by dilation of lymphatic vessels. It may occur as an isolated lesion or, more often, represent the surface component of a deep orbital lymphangioma. Case. We report a case of a conjunctival lymphangioma on a 58-year-old male that had simultaneously an upper respiratory tract infection. Excision and biopsy confirmed the nature of the lesion, and there has been no relapse to date. Conclusion. Conjunctival lymphangioma is a rare condition in which the diagnose, must be kept in mind in patients with a red eye resistance to topical therapy and in association with an upper respiratory tract infection. Finally, it is also necessary to be aware of possible recurrence of the lesion.


Development and results of the epilepsy surgery in Armenia: hope for a better future.
We present our experience with the national epilepsy surgery program in Armenia by tracing the development of epilepsy surgery in the largest pediatric neurology department at "Arabkir" Medical Center. This development was possible on the basis of a strong collaboration with the Epilepsy Surgery center at the University Hospital "Sofia St. Ivan Rilski," Sofia, Bulgaria. Our material included 28 consecutive patients with lesional drug-resistant epilepsy evaluated. All patients underwent 3 T MRI and Video-EEG monitoring. Brain 18FDG-PET was done in 13 patients in St. Petersburg. Fifteen patients (53%) had preoperative neuropsychological examination before surgery. All operations were done by the same neurosurgical team on site in Arabkir Hospital. The majority of the patients in our cohort benefited from the epilepsy surgery as 25 (89%) are free of disabling seizures (Engel class I) and three patients (11%) did not improve substantially (Engel class IV). Eleven patients (39%) are already ASM-free after surgery, 4 (14%) are on monotherapy, 11(39%) get two drugs, and 2(7%) are on polytherapy, one of them still continues having seizures. In 12 patients (43%), we were able either to withdraw therapy or to decrease one of the ASM. We believe that, although small, yet encompassing patients along the usual age spectrum and with the most frequent pathologies of drug-resistant epilepsies, our experience can serve as a model to develop epilepsy surgery in countries with limited resources.


[Hypertension and perceived material insecurity in a disadvantaged Caribbean population].
To assess the relationship between hypertension and perceived material insecurity in a disadvantaged Caribbean population. We used data from a cross-sectional study involving 2420 disadvantaged subjects aged 18-69 years, included consecutively at three Guadeloupian health centers. Hypertension was diagnosed over two consultations with a total of six blood pressure measurements. Perceived material insecurity was assessed using a closed-ended question. The prevalence of hypertension was estimated at 17.7% among subjects who believed their material situation would improve in the future, at 28.2% among those who believed it would remain the same, and at 43.3% among those who believed it would deteriorate. A multivariate logistic regression analysis showed that hypertension risk more than doubled (OR: 2.35 - P: 0.002) among subjects who believed that their material situation would deteriorate in the future compared to those who believed that their situation would improve, with no significant sex-related differences. This relationship was especially strong among subjects aged 40 years or more (OR: 3.30 - P<10(-3)), and among subjects with low education level (OR: 3.81 - P: 0.003), but was independent of the other tested variables. In this disadvantaged population, perceived material insecurity is a psychosocial factor strongly associated with hypertension, independently of subjects' risk behaviors. Subjects aged 40 years or more and subjects with a low education level seem the most vulnerable.


Audiogram, body mass, and basilar papilla length: correlations in birds and predictions for extinct archosaurs.
The inner ear in the group of archosaurs (birds, crocodilians, and extinct dinosaurs) shows a high degree of structural similarity, enabling predictions of their function in extinct species based on relationships among similar variables in living birds. Behavioral audiograms and morphological data on the length of the auditory sensory epithelium (the basilar papilla) are available for many avian species. By bringing different data sets together, we show that body mass and the size of the basilar papilla are significantly correlated, and the most sensitive frequency in a given species is inversely related to the body mass and the length of the basilar papilla. We also demonstrate that the frequency of best hearing is correlated with the high-frequency limit of hearing. Small species with a short basilar papilla hear higher frequencies compared with larger species with a longer basilar papilla. Based on the regression analysis of two significant correlations in living archosaurs (best audiogram frequency vs body mass and best audiogram frequency vs papillar length), we suggest that hearing in large dinosaurs was restricted to low frequencies with a high-frequency limit below 3 kHz.


Proximate Composition and Functional Properties of Mushroom Flours from Ganoderma spp., Omphalotus olearius (DC.) Sing. and Hebeloma mesophaeum (Pers.) Quél. Used in Nasarawa State, Nigeria.
The proximate composition and functional properties of three edible mushroom (Ganoderma spp., Omphalotus olearius (DC.) Sing. and Hebeloma mesophaeum (Pers.) Quél.) flours used in Nasarawa state, Nigaria were investigated using standard analytical techniques. The samples contained crude protein in the range of 18.5% in Omphalotus olearius to 21.5% in Ganoderma spp. Crude fat varied with values ranging from 6.9% in Ganoderma spp. to 8.7% in Omphalotus olearius. Other proximate composition values were in the following ranges: moisture content 10.0 - 11.1%, ash 7.3 - 8.3%, crude fibre 2.8 - 3.5% and carbohydrate (by difference) 50.3 - 50.9%. The range values of functional properties were: foaming capacity 101.8 - 131.5%, foaming stability 51.0 - 54.0%, water absorption capacity 260.0 - 390.0%, oil absorption capacity 450 - 480%, oil emulsion capacity 57.3 - 61.0mLg- 1, least gelation concentration 12.0 - 14.0% and bulk density 230.0 - 410.0gmL-1. The results showed that these nutrient rich mushroom flours under investigation may prove useful in the formulation of different food products where foaming, emulsification, retention of flavour and palatability as well as gel formation are required.


Protective effect of betaine against lead-induced testicular toxicity in male mice.
Lead (Pb) is an environmental toxicant reported to impair male reproductive system. Betaine is a natural product which has promising beneficial effects against oxidative stress. In this experimental study, we evaluated the ameliorative effect of betaine on sperm quality and oxidative stress induced by lead (Pb) in the testis of adult male mice. Sixty male Kunming mice were divided equally into four groups: control group, betaine group (1% in drinking water), lead group (100 mg kg-1 bw-1 day-1 ) and betaine + lead group. In the last group, mice were supplemented with betaine for two weeks prior to the initiation of lead treatment and concurrently during lead treatment for 3 weeks until sacrificed. Our results indicated that in the lead-administrated group, body weights together with sperm count were significantly decreased (p < .05). The numbers of abnormal sperms were found to be higher in lead-treated mice. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (Cat) were significantly reduced, while the level of malondialdehyde (MDA) content was increased in the testis tissue following lead treatment. The mRNA levels of antioxidant-related genes (SOD1, GPX1 and CAT) were significantly decreased in the lead group. Betaine enhanced these parameters in betaine + lead group. In testis histology span, Johnson score was decreased (p < .05) in lead group and co-treatment with betaine increased Johnson score significantly in betaine + lead group. These results indicate that betaine improves sperm quality and ameliorate oxidative damage in testis of mice exposed to lead.


The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches.
Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.


In between: gypsy in Drosophila melanogaster reveals new insights into endogenous retrovirus evolution.
Retroviruses are RNA viruses that are able to synthesize a DNA copy of their genome and insert it into a chromosome of the host cell. Sequencing of different eukaryote genomes has revealed the presence of many such endogenous retroviral sequences. The mechanisms by which these retroviral sequences have colonized the genome are still unknown, and the endogenous retrovirus gypsy of Drosophila melanogaster is a powerful experimental model for deciphering this process in vivo. Gypsy is expressed in a layer of somatic cells, and then transferred into the oocyte by an unknown mechanism. This critical step is the start of the endogenization process. Moreover gypsy has been shown to have infectious properties, probably due to its envelope gene acquired from a baculovirus. Recently we have also shown that gypsy maternal transmission is reduced in the presence of the endosymbiotic bacterium Wolbachia. These studies demonstrate that gypsy is a unique and powerful model for understanding the endogenization of retroviruses.


Butyrate-mediated acquisition of chemoresistance by human colon cancer cells.
Butyrate is a short-chain fatty acid produced by the intestinal microflora and it not only induces apoptosis but also inhibits the proliferation of cancer cells. Recently, it has been reported that butyrate may cause resistance in colon cancer cells. Therefore, we investigated the effects of increased resistance to butyrate in HCT116 colon cancer cells. We established HCT116 cells resistant to butyrate (HCT116/BR) by treating HCT116 parental cells (HCT116/PT) with increasing concentrations of butyrate to a maximum of 1.6 mM for 3 months. The butyrate concentrations that inhibited cell growth by 50% (IC50) were 0.508 and 5.50 mM in HCT116/PT and HCT116/BR cells. The values after treatment with paclitaxel, 5-fluorouracil (5-FU), doxorubicin and trichostatin A (TSA) were 2.42, 2.36, 4.31 and 11.3-fold higher, respectively, in HCT116/BR cells compared with HCT116/PT cells. The protein expression of drug efflux pumps, such as P-glycoprotein (P-gp), breast cancer-resistant protein (BCRP) and the multidrug resistance associated protein 1 (MRP1), did not differ between HCT116/PT and HCT116/BR cells. The expression level of the anti-apoptotic Bcl-xL protein was increased while those of pro-apoptotic Bax and Bim proteins were reduced in HCT116/BR cells. There were no significant differences in cell motility and invasion. This study suggests that exposure of colon cancer cells to butyrate results in development of resistance to butyrate, which may play a role in the acquisition of chemoresistance in colon cancer.


Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
To assess whether low response to clopidogrel influences cardiovascular outcome after coronary stent implantation in a consecutively measured cohort of patients with coronary stent implantation. A total of 379 consecutive patients with symptomatic coronary artery disease (CAD), (stable angina n = 206 and acute coronary syndrome, n = 173) treated with percutaneous coronary stenting were enrolled in this trial. Responsiveness to clopidogrel was assessed by ADP (20 micromol/L)-induced aggregometry at least 6 h (mean 34.8+/-25.9 h) after administration of a loading dose of 600 mg clopidogrel. Platelet inhibition < 30% was defined as low response to clopidogrel. At 3-month follow-up, the primary outcome of a combined major cardiovascular event including non-fatal myocardial infarction, non-fatal ischaemic stroke, or cardiovascular death was evaluated. Twenty-two patients (5.8%) were classified as low responders. Compared with patients who adequately responded to clopidogrel, a low responder had a significantly higher risk of major cardiovascular events [22.7 vs. 5.6%; odds ratio, 4.9; 95% confidence interval (CI), 1.66-14.96; P = 0.004]. After adjustment for other factors influencing cardiovascular outcome, low response to clopidogrel and severe left ventricular dysfunction were independently associated with a major cardiovascular event within 3 months (hazard ratio for low response to clopidogrel, 3.71; 95% CI, 1.08-12.69; P = 0.037). Low response to clopidogrel in patients with symptomatic CAD treated by stenting significantly enhances the occurrence of cardiovascular events and death. The evaluation of low response to clopidogrel may help to identify patients at increased risk who may benefit from intensified antiplatelet strategy.


Mechanisms of reduction of antitumor drug toxicity by liposome encapsulation.
Actinomycin D, when encapsulated within liposomes, has been previously shown to be less toxic to mice than nonencapsulated actinomycin D, but to retain its tumoricidal activity. We have compared the toxic effects of Act D encapsulated either in the aqueous phase or in the lipid phase of liposomes (APL and LPL, respectively), and the nonencapsulated Act D on the blood forming system, on cell proliferation in the intestine, and on antibody production by spleen lymphocytes. At a single dose of 0.4 mg/kg, APL-encapsulated Act D wass less toxic to white blood cells and to the nucleated cells and colony-forming stem cells of the bone marrow. During toxicity in the proliferating intestinal cells, measured by 3H-thymidine incorporation, was reduced by about a factor of 4 with encapsulation in APL, particularly 24 hours after Act D administration. The toxiciaty of LPL-encapsulated Act D to both the blood-forming system and the intestinal proliferating cells was, however, not significantly different from that of the nonencapsulated Act D. Effects of Act D on the antibody production by spleen cells, determined by the "limited hemolysis in agar" assay, showed that immunosuppression was most markedly reduced by liposome encapsulation either in APL or in LPL, when the drug was given one day before the antigen. These findings are important for considerations of liposome application in cancer chemotherapy.


Hatching asynchrony impacts cognition in male zebra finches.
Conditions experienced early in life can shape brain development and later cognition. Altricial songbirds are particularly vulnerable to early environmental perturbations. Research on "Developmental Stress" in songbirds has addressed how early-life conditions may impair song learning and has been extended to consider other components of adult phenotype. Early-life challenges ranging from ectoparasites to competition with siblings have been shown to compromise song learning and other measures of cognition, as well as behavioral strategy. Here, we examined both the effects of hatching asynchrony and early-life immune system challenge with lipopolysaccharide (LPS) on neophobia, song learning, motoric learning, and spatial cognition in male zebra finches (Taeniopygia guttata). We found that hatch order had a significant impact on motoric and spatial learning, such that later hatched males performed better than first and second hatched birds. In contrast, LPS treatment only impacted motoric learning and neither hatch order nor immune system challenge impacted song quality, song learning accuracy, or neophobia. These results are consistent with a growing body of evidence that conditions early in life can improve cognitive performance at adulthood. Moreover, these findings indicate that hatch order is an important factor to consider in developmental studies in asynchronously hatching birds.


Toughening Double-Network Hydrogels by Polyelectrolytes.
The Hoffmeister effect of inorganic salts is verified as a promising way to toughen hydrogels, however, the high concentration of inorganic salts may be accompanied by poor biocompatibility. In this work, it is found that polyelectrolytes can obviously elevate the mechanical performances of hydrogels through the Hoffmeister effect. The introduction of anionic poly(sodium acrylate) into poly(vinyl alcohol) (PVA) hydrogel induces the aggregation and crystallization of the PVA to boost the mechanical properties of the resulting double-network hydrogel: elevation of 73, 64, 28, 135, and 19 times in the tensile strength, compressive strength, Young's modulus, toughness, and fracture energy compared with poly(acrylic acid), respectively. It is noteworthy that the mechanical performances of the hydrogels can be flexibly tuned by the variation of polyelectrolyte concentration, ionization degree, relative hydrophobicity of the ionic component, and polyelectrolyte type in a wide range. This strategy is verified to work for other Hoffmeister-effect-sensitive polymers and polyelectrolytes. Also, the introduction of urea bonds into the polyelectrolyte can further improve the mechanical properties and antiswelling capability of hydrogels. As a biomedical patch, the advanced hydrogel can efficiently inhibit hernia formation and promote the regeneration of soft tissues in an abdominal wall defect model.


Simulating the physician as healthcare manager: An innovative course to train for the manager role.
During their formal studies medical students acquire extensive medical expertise. However, the medical profession demands additional competencies, such as those involved in efficient resource allocation, business administration, development, organization, and process management in the healthcare system. At present students are not sufficiently prepared for the physician's role as manager. In response, we designed the seminar course, MeCuM-SiGma, to impart basic knowledge about healthcare policy and management to students of medicine. This project report describes our teaching strategies and the initial evaluation of this educational project. In this semester-long, seminar course introduced in 2010, medical students gather experience with the competencies mentioned above as well as learn basic management skills. The course is offered each winter semester, and students sign up to attend voluntarily; course coordination and organization is done on a voluntary basis by physicians and employees of the Mentoring Office (MeCuM-Mentor) at the Medical School of the Ludwig Maximilian University (LMU) in Munich, Germany. The course is open to all students enrolled at the two medical schools in Munich. During the first part of this elective, students learn about the basic principles of the German political and healthcare systems in case-based, problem-based tutorials led by trained tutors and in lectures held by experts. In the second part of the course students take on the roles of the University Hospital's executive board of directors and supervisory board to work on an existing hospital project as a group within the scope of a simulation. This phase of the course is accompanied by workshops conducted in cooperation with university-based and off-campus partners that address the procedural learning objectives (teamwork, project management, negotiation strategies, etc.). A suitable, authentic issue currently facing the hospital is selected in advance by the course organizers in coordination with the hospital's executive board. Students then work on this issue in the third and final phase of the course under the supervision of tutors and with assistance from hospital employees. At the end of the course the students formally present the results of their work to the hospital's executive and supervisory boards. The course undergoes written student evaluation, a round of oral feedback, evaluation of the final projects, and feedback from the hospital's executive and supervisory boards. All attendees to date have reported a substantial gain in general knowledge and increased knowledge about the healthcare system, and rate the relevance of the course as being high. The majority felt the content was important for their future practice of medicine. Overall, students evaluated the course very positively [overall rating on a six-point grading scale (1=excellent; 6=unsatisfactory): 1.28 (mean)±0.45 (standard deviation)]. The importance of the physician's role as manager in medical organizations and as a guiding force in the healthcare system is neglected in medical degree programs. Our seminar course attempts to address this shortcoming, is the object of great interest and receives positive evaluations from seminar participants, our cooperative partners and the executive and supervisory boards of the University Hospital in Munich.


Factors that may influence the preparation of standards of procedures for dealing with mass-casualty incidents.
General hospitals in Israel are required to develop standards of procedures (SOPs) to facilitate the management of mass-casualty incidents (MCIs). These SOPs represent the initial step in a continuous process, providing guidelines for hospitals to manage MCIs in an organized and efficient manner. Evaluation of the preparedness levels of hospitals in dealing with MCIs is required in order to promote an effective response, and to identify factors that might impact the quality of SOPs. The aim of this study was to identify the characteristics of hospitals that have an impact on the preparation of SOPs. An evaluation tool was developed to assess the SOPs from 22 hospitals during the management of a MCI. The results of the evaluations were analyzed, in relation to the size, trauma capabilities, ownership, geographic location, urban versus rural status of the hospitals, the proximity to other hospitals, participation in drills during the year prior to the evaluation, and number of actual MCIs the hospital managed in the past three years. The evaluation scores of the SOPs of 11 of the 22 hospitals (50%) were very high, so their SOPs did not require modifications. The SOPs of four hospitals (18%) were rated highly, requiring only minor modifications. The SOPs of four hospitals (18%) received poor ratings, requiring major modifications, and three hospitals (14%) were found to have incomplete SOPs and received very poor ratings. No significant differences were found between the ratings of SOPs in relation to the different characteristics of the hospitals analyzed. A low correlation between the level of SOPs and the number of MCIs that the hospital managed was found (r = 0.266, NS). The tool developed to evaluate the quality of the SOPs of hospitals to manage MCIs was logistically feasible and capable of differentiating between hospital SOPs. The comprehensiveness and completeness of the SOPs appears to be unrelated to the characteristics of the hospitals included in this study. Of particular note was the lack of a significant correlation between the SOP rating and the number of actual MCIs managed by a hospital.


[Genetic characterization of norovirus isolated in an outbreak of gastroenteritis in Jiangsu province].
Objective: To analyze the genetic characterization of norovirus isolated in an outbreak of gastroenteritis in Jiangsu province. Methods: Extracted viral RNA from the swab samples of cases of acute gastroenteritis outbreak in Jiangsu province on December 16-27, 2016 was reversely transcribed to cDNA, and partial RNA-dependent RNA polymerase sequence and complete capsid sequence (VP1) were amplified by RT-PCR. Amplification products were sequenced for the analysis of genetic characteristics. Results: Based on sequence alignment, the variant shared a high level of identity with the strain GⅡ.g isolated in Spain and Finland (98.7%) in the RNA-dependent RNA polymerase region, and with the strain GⅡ.1 isolated in American (99.4%) in the VP1. The recombination was determined by using software Simplot, and the breakpoint of recombination was located in the ORF1/2 overlap region at position 5 106 of VP1. The result of amino acids alignment in capsid region showed that there were no mutations in the amino acids of the predicted epitopes and receptor binding site Ⅰ-Ⅲ, but a unique amino acid change was detected at position 132 (N-S). Conclusion: The norovirus isolated in the outbreak of gastroenteritis in Jiangsu province was a rare recombinant norovirus variant GⅡ.g-GⅡ.1.


[Synchronous pancreatic and rectal cancer--clinical note].
The study is presenting a case of the patient with synchronous pancreatic and rectal cancer. Rectal cancer was detected before pancreatic surgery based on the clinical findings and additional tests. Pancreatic and rectal resection performed as one-step procedure was the optimal surgical treatment in the analysed case.


Dramatic subperiosteal bone formation following physeal injury in patients with myelomeningocele.
We present five cases of dramatic subperiosteal bone formation following fracture of the distal femoral physis in children with myelomeningocele. These fractures often go unrecognized due to lack of displacement and/or pain. Children present with a swollen, warm extremity and often systemic signs of inflammation, but rarely any pain or history of trauma. The dramatic radiographic appearance can cause a diagnostic dilemma. We present these cases in order to familiarize the clinician with the oftentimes dramatic appearance of this injury.


Infection caused by vancomycin-resistant Streptococcus sanguis II.
A patient with bacteremia caused by vancomycin-resistant Streptococcus sanguis II is presented. This rare occurrence suggests that vancomycin may not be a completely reliable antibiotic in the treatment of infections due to viridans species of the genus Streptococcus. Gram-positive isolates from blood and otherwise sterile body fluids should be tested for susceptibility to vancomycin.


Development of nervous systems to metamorphosis in feeding and non-feeding echinoid larvae, the transition from bilateral to radial symmetry.
The development of nervous system (NS) in the non-feeding vestibula larva of the sea urchin, Holopneustes purpurescens, and the feeding echinopluteus larva of Hemicentrotus pulcherrimus was examined by focusing on fate during metamorphosis. In H. purpurescens, the serotonergic NS (SerNS) appeared simultaneously and independently in larval tissue and adult rudiment, respectively, from 3-day post-fertilization. In 4-day vestibulae, an expansive aboral ganglion (450 x 100 mum) was present in the larval mid region that extended axons toward the oral ectoderm. These axons diverged near the base of the primary podia. An axonal bundle connected with the primary podia and the rim of vestopore on the oral side. Thus, the SerNS of the larva innervated the rudiment at early stage of development of the primary podia. This innervation was short-lived, and immediately before metamorphosis, it disappeared from the larval and adult tissue domains, whereas non-SerNS marked by synaptotagmin remained. The NS of 1-month post-fertilization plutei of H. pulcherrimus comprised an apical ganglion (50 x 17 mum) and axons that extended to the ciliary bands and the adult rudiment (AR). A major basal nerve of serotonergic and non-serotonergic axons and a minor non-serotonergic nerve comprised the ciliary band nerve. In 3-month plutei, axonal connection among the primary podia in the neural folds completed. The SerNS never developed in the AR. Thus, there was distinctive difference between feeding- and non-feeding larvae of the above sea urchins with respect to SerNS and the AR.


Does residual microscopic disease after chemoradiotherapy for locally advanced rectal cancer translate into a good clinical outcome?
This study aimed to assess the progression-free and overall survival of patients with residual microscopic disease following neoadjuvant chemoradiotherapy and rectal resection for locally advanced rectal cancer. Two-hundred and thirty-four consecutive rectal cancer patients who had neoadjuvant chemoradiotherapy followed by radical resection (from May 2000 to April 2012) were divided according to pathological tumour response: residual microscopic disease (MIC), complete response (pCR) and partial/no response (non-CR). Data on the neoadjuvant regime, treatment-to-surgery interval, final pathology, type of operation, operative time, postoperative complications, length of hospital stay, disease recurrence and mortality were compared between the groups. There were 13 (5.5%) MIC patients, 48 (20.5%) with pCR and 173 (73.9%) with non-CR group. The groups were demographically comparable. MIC patients had more retrieved lymph nodes compared with the non-CR and pCR patients (median 13 compared with 8 and 10, respectively, P = 0.0086). The 5-year overall survival rates were 93.4% for the pCR and MIC patients vs 82.1% for the non-CR patients (P = 0.0324). The 5-year progression-free survival was 85.2% for the pCR and MIC patients vs 73.8% for the non-CR patients (P = 0.086). We have identified and assessed a new pathological subgroup of rectal cancer patients who had residual microscopic disease after neoadjuvant therapy. The survival analysis aligned them closely with pCR patients.


[WHO growth standards for infants and young children].
The growth pattern of healthy breastfed infants deviates to a significant extent from the NCHS/WHO international reference. In particular, this reference is inadequate because it is based on predominantly formula-fed infants, as are most national growth charts in use today. The WHO multicentre growth reference study (MGRS), aimed at describing the growth of healthy breastfed infants living in good hygiene conditions, was conducted between 1997 and 2003 in 6 countries from diverse geographical regions: Brazil, Ghana, India, Norway, Oman and the United States. The study combined a longitudinal follow-up of 882 infants from birth to 24 months with a cross-sectional component of 6669 children aged 18-71 months. In the longitudinal follow-up study, mothers and newborns were enrolled at birth and visited at home a total of 21 times at weeks 1, 2, 4 and 6; monthly from 2-12 months; and bimonthly in the 2nd year. The study populations lived in socioeconomic conditions favorable to growth. The individual inclusion criteria for the longitudinal component were: no known health or environmental constraints to growth, mothers willing to follow MGRS feeding recommendations (i.e., exclusive or predominant breastfeeding for at least 4 months, introduction of complementary foods by 6 months of age and continued breastfeeding to at least 12 months of age), no maternal smoking before and after delivery, single-term birth and absence of significant morbidity. Term low-birth-weight infants were not excluded. The eligibility criteria for the cross-sectional component were the same as those for the longitudinal component with the exception of infant feeding practices. A minimum of 3 months of any breastfeeding was required for participants in the study's cross-sectional component. Weight-for-age, length/height-for-age, weight-for-length/height and body mass index-for-age percentile and Z-score values were generated for boys and girls aged 0-60 months. The full set of tables and charts is presented on the WHO website (www.who.int/childgrowth/en), together with tools such as software and training materials that facilitate their application. The WHO child growth standards were derived from children who were raised in environments that minimized constraints to growth, such as poor diets and infection. In addition, their mothers followed healthy practices such as breastfeeding their children and not smoking during and after pregnancy. The standards depict normal human growth under optimal environmental conditions and can be used to assess children everywhere, regardless of ethnicity, socioeconomic status and type of feeding. The standards explicitly identify breastfeeding as the biological norm and establish the breastfed child as the normative model for growth and development. They have the potential to significantly strengthen health policies and public support for breastfeeding. The pooled sample from the 6 participating countries allowed the development of a truly international reference that underscores the fact that child populations grow similarly across the world's major regions when their health and care needs are met. It also provides a tool that is timely and appropriate for the ethnic diversity seen within countries and the evolution toward increasingly multiracial societies in the Americas and Europe as elsewhere in the world. The WHO standards provide a better tool to monitor the rapid and changing rate of growth in early infancy. They also demonstrate that healthy children from around the world who are raised in healthy environments and follow recommended feeding practices have strikingly similar patterns of growth.


Use of participatory epidemiology to compare the clinical veterinary knowledge of pastoralists and veterinarians in East Africa.
Because of severe resource and logistical constraints in large areas of Africa, disease surveillance systems need to maximize the use of information provided by livestock keepers and make correct interpretations of indigenous livestock knowledge. This paper describes the use of participatory epidemiology (PE) to compare the names, clinical signs and epidemiological features of cattle diseases as perceived by pastoralists and veterinarians. Using results from two previous studies with pastoralists in southern Sudan and Kenya, provisional translations of local disease names into modem veterinary terminology were used to develop a matrix scoring method for use with veterinarians. Matrix scoring data from pastoralists and veterinarians were then compared using simple visual comparison of summarized matrices, hierarchical cluster analysis and multidimensional scaling. The results showed good agreement between pastoralists' and veterinarians' disease names and diagnostic criteria. The matrix scoring method was easy to use and appropriate for use in under-resourced areas with minimal professional support or laboratory services. Matrix scoring could be used to assist livestock disease surveillance workers to design surveillance systems that make better use of pastoralist's indigenous knowledge and correctly interpret local disease names. The method should be combined with conventional veterinary investigation methods where feasible.


Accuracy of Orbscan II in the assessment of posterior curvature in patients with myopic LASIK.
To evaluate the accuracy of Orbscan II measurements in assessing posterior corneal curvature in patients undergoing myopic LASIK. Using the Orbscan II, posterior corneal curvature was assessed pre- and postoperatively in 304 eyes that underwent myopic LASIK. The radius of curvature and corneal refractive power in diopters (D) were compared using the paired sample t test. The mean pre- and postoperative radius of posterior corneal curvature were 6.49 +/- 0.26 mm and 6.35 +/- 0.30 mm, respectively. Mean pre- and postoperative posterior corneal power were -6.17 +/- 0.25 D and -6.32 +/- 0.30 D, respectively, and the difference (0.14 +/- 0.14 D) was statistically significant (P < .01). Although the derived value for the power of the postoperative LASIK posterior corneal surface is overestimated using the Orbscan II, this small difference may not be clinically important. Orbscan II measurements can therefore be used (with caution) to measure posterior corneal curvature in patients with myopic LASIK for the assessment of intraocular lens power based on the Gaussian optics formula.


Vascular autorescaling of fMRI (VasA fMRI) improves sensitivity of population studies: A pilot study.
The blood oxygenation level-dependent (BOLD) signal is widely used for functional magnetic resonance imaging (fMRI) of brain function in health and disease. The statistical power of fMRI group studies is significantly hampered by high inter-subject variance due to differences in baseline vascular physiology. Several methods have been proposed to account for physiological vascularization differences between subjects and hence improve the sensitivity in group studies. However, these methods require the acquisition of additional reference scans (such as a full resting-state fMRI session or ASL-based calibrated BOLD). We present a vascular autorescaling (VasA) method, which does not require any additional reference scans. VasA is based on the observation that slow oscillations (<0.1Hz) in arterial blood CO2 levels occur naturally due to changes in respiration patterns. These oscillations yield fMRI signal changes whose amplitudes reflect the blood oxygenation levels and underlying local vascularization and vascular responsivity. VasA estimates proxies of the amplitude of these CO2-driven oscillations directly from the residuals of task-related fMRI data without the need for reference scans. The estimates are used to scale the amplitude of task-related fMRI responses, to account for vascular differences. The VasA maps compared well to cerebrovascular reactivity (CVR) maps and cerebral blood volume maps based on vascular space occupancy (VASO) measurements in four volunteers, speaking to the physiological vascular basis of VasA. VasA was validated in a wide variety of tasks in 138 volunteers. VasA increased t-scores by up to 30% in specific brain areas such as the visual cortex. The number of activated voxels was increased by up to 200% in brain areas such as the orbital frontal cortex while still controlling the nominal false-positive rate. VasA fMRI outperformed previously proposed rescaling approaches based on resting-state fMRI data and can be readily applied to any task-related fMRI data set, even retrospectively.


Early identification of pneumonia patients at increased risk of Middle East respiratory syndrome coronavirus infection in Saudi Arabia.
The rapid and accurate identification of individuals who are at high risk of Middle East respiratory syndrome coronavirus (MERS-CoV) infection remains a major challenge for the medical and scientific communities. The aim of this study was to develop and validate a risk prediction model for the screening of suspected cases of MERS-CoV infection in patients who have developed pneumonia. A two-center, retrospective case-control study was performed. A total of 360 patients with confirmed pneumonia who were evaluated for MERS-CoV infection by real-time reverse transcription polymerase chain reaction (rRT-PCR) between September 1, 2012 and June 1, 2016 at King Abdulaziz Medical City in Riyadh and King Fahad General Hospital in Jeddah, were included. According to the rRT-PCR results, 135 patients were positive for MERS-CoV and 225 were negative. Demographic characteristics, clinical presentations, and radiological and laboratory findings were collected for each subject. A risk prediction model to identify pneumonia patients at increased risk of MERS-CoV was developed. The model included male sex, contact with a sick patient or camel, diabetes, severe illness, low white blood cell (WBC) count, low alanine aminotransferase (ALT), and high aspartate aminotransferase (AST). The model performed well in predicting MERS-CoV infection (area under the receiver operating characteristics curves (AUC) 0.8162), on internal validation (AUC 0.8037), and on a goodness-of-fit test (p=0.592). The risk prediction model, which produced an optimal probability cut-off of 0.33, had a sensitivity of 0.716 and specificity of 0.783. This study provides a simple, practical, and valid algorithm to identify pneumonia patients at increased risk of MERS-CoV infection. This risk prediction model could be useful for the early identification of patients at the highest risk of MERS-CoV infection. Further validation of the prediction model on a large prospective cohort of representative patients with pneumonia is necessary.


[Choline improves lipopolysaccharide-induced central nervous system inflammatory response and cognitive dysfunction in mice].
To assess the effect of choline in ameliorating lipopolysaccharide (LPS)-induced central nervous system inflammation and cognitive deficits in mice and explore the underlying mechanism. Seventy-two mice were randomized into saline control group, LPS group, choline intervention group and choline control group. In the latter two groups, the mice received pretreatment with intraperitoneal injections of choline (40 mg/kg, 3 times daily for 3 consecutive days) prior to microinjection of LPS into the lateral cerebral ventricle to induce central nervous system inflammation; in saline and LPS groups, the mice were pretreated with saline in the same manner before intraventicular injection of artificial cerebrospinal fluid. Choline treatment was administered in the mice till the end of the experiment. The locomotor activity and spatial learning and memory capacity of the mice were examined. The expressions of Iba1 protein and proinflammatory cytokines (TNF-α and IL-β) I the hippocampal dentate gyrus, and the expressions of α 7nAchR, p38 MAPK and phosphorylated p38 MAPK in the hippocampus of the mice were detected. Water maze test showed that compared with the saline control group, the mice in LPS group exhibited significantly reduced platform crossings (P<0.05), which was significantly increased by choline pretreatment (P<0.05). The mice pretreated with LPS expressed obviously increased levels of IBA-1 protein, TNF-α, and IL-1β in the hippocampus (P<0.01), and choline pretreatment significantly lowered the expressions of IBA-1 protein and IL-1β (P<0.05). The phosphorylation level of p38 MAPK increased significantly after LPS pretreatment (P<0.05), and was reduced by choline pretreatment (P<0.05); α 7nAchR expression increased significantly in choline intervention group as compared with that in the other 3 groups (P<0.05). Choline can probably antagonize LPS-induced hippocampal p38 MAPK phosphorylation in mice via the α 7nAchR signaling pathway to protective against LPS-induced neuroinflammation and cognitive impairment in mice.


Thymic inhibition of myelopoietic proliferation.
Homeostasis may be viewed as the dynamic balance reached between cellular production and loss. The effectors of proliferation are thought to be tissue-specific humoral substances. Inhibitory substances appear to negate the proliferate effects of activator substances. We report here that conditioned medium from cultures of murine "nonlymphoid" adherent thymus cells in a source of a potent myelopoietic inhibitor substance(s). Examination of the inhibitor(s) in the soft-agar clonogenic assay show it to abrogate both the 10-day granulocyte-macrophage colony-forming cell (GM-CFC) and the 25-day monocyte-macrophage colony-forming cell (M-CFC). The inhibition is most significant when the thymus-conditioned medium (TCM) is present upon culture initiation. TCM added at a time after soft-agar initiation (day 6) also results in significant clonogenic inhibition. We have characterized the inhibitor as potent on the basis that volume ratios of inhibitor to L-cell colony-stimulating factor (CSF) as low as 1 part to 40 parts will give near total inhibition of both GM-CFC and M-CFC clonogenic growth. The inhibitor is dialyzable, has a molecular weight of less than 1000, is not significantly cytotoxic, and its effects are reversible with washing.


Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells.
Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.


Bulking agents in the treatment of stress urinary incontinence: history, outcomes, patient populations, and reimbursement profile.
Stress urinary incontinence (SUI) can be defined as involuntary loss of urine during a period of increased abdominal pressure and in the absence of detrusor activity. Bulking agents used in the urethra are one of the newer but established technologies for the treatment of SUI. An understanding of the demographics of SUI will help in the selection of patients for bulking agent therapy. Knowledge of available materials, including their positive and negative aspects, is also required. Autologous fat, silicone beads, collagen, carbon particles, and polytetrafluoroethylene paste have all demonstrated success to some degree, but none have met both criteria for success (remaining efficacious over time and maintaining a low side-effect profile). An implantable solution of ethylene vinyl alcohol suspended in dimethyl sulfoxide, currently in clinical testing and review, shows minimal foreign body reaction and is one option being investigated to address patient needs for improved bulking therapy.


Simple and Rapid Method by Ultra High-Performance Liquid Chromatography (UHPLC) with Ultraviolet Detection for Determination of Efavirenz in Plasma: Application in a Preclinical Pharmacokinetic Study.
A simple and rapid ultra-high-performance liquid chromatography (UHPLC) method for determination of efavirenz (EFV) in plasma was developed and applied in a preclinical pharmacokinetic study. The method involves only addition of acetonitrile to precipitation of plasma proteins followed by solvent evaporation. The mobile phase consisted of methanol, acetonitrile and 0.1 M formic acid (20:50:30) at a flow rate of 0.3 mL/min with run time of 5 min. A CSH C18 column and a UHPLC-UV system operating at 245 nm were used. There was a linear response in the range of 0.078 to 10 μg/mL, and the equation was obtained by weighting (1/x2) with r2 = 0.9965. The pharmacokinetic disposition of EFV was investigated in rabbits (two groups, n = 7) following a single intravenous administration (IV group) at a dose of 2.7 mg/kg and a single oral administration (oral group) of EFV co-administered with lamivudine (3TC) and tenofovir (TNF) at a dose of 50, 25 and 25 mg, respectively. The study demonstrated the applicability of the method for determination of EFV in plasma without interference from other co-administered drugs, and the pharmacokinetic parameters were calculated. The method showed advantages over other methods in the literature, such as simplicity of sample processing and fast results.


Colour recognition at large visual eccentricities in normal observers and patients with low vision.
When we look at our spatial environment we have the feeling that the whole visual field is coloured, yet the density of cone photoreceptors decreases considerably as eccentricity increases. We investigated colour perception (coloured/noncoloured), colour naming and whether colour helps object recognition at eccentricities varying from 0 degrees to 80 degrees in healthy observers and patients with low vision. We found that colours can be perceived and even identified above chance at very large eccentricities (60 degrees). When asked to categorize coloured and grey level objects as edible/nonedible, both healthy observers and patients with low vision showed better performance for coloured edible objects at 50 degrees suggesting that colour is used for object recognition in conditions of degraded form perception.