Adiposity and the development of diabetes in mouse genetic models.
While it is certain from the analysis of transgenic models of lipodystrophy that a critical mass of adipose tissue is necessary to prevent the development of diabetes, the reasons why diabetes develops in one obese individual and not in another need to be further investigated. This is also one of the major questions associated with the current obesity epidemic and the development of the metabolic syndrome. The severe lipodystrophic models do not really address this big problem. In this presentation, we point out that models exist among inbred strains of mice that can contribute towards finding answers to the diabetes found in the metabolic syndrome. The differences responsible for the phenotypic variations are undoubtedly multifactorial and involve many genes, but there are powerful genetic resources to investigate these problems.


Lung volumes and lung volume recruitment in ARDS: a comparison between supine and prone position.
The use of positive end-expiratory pressure (PEEP) and prone position (PP) is common in the management of severe acute respiratory distress syndrome patients (ARDS). We conducted this study to analyze the variation in lung volumes and PEEP-induced lung volume recruitment with the change from supine position (SP) to PP in ARDS patients. The investigation was conducted in a multidisciplinary intensive care unit. Patients who met the clinical criteria of the Berlin definition for ARDS were included. The responsible physician set basal PEEP. To avoid hypoxemia, FiO2 was increased to 0.8 1 h before starting the protocol. End-expiratory lung volume (EELV) and functional residual capacity (FRC) were measured using the nitrogen washout/washin technique. After the procedures in SP, the patients were turned to PP and 1 h later the same procedures were made in PP. Twenty-three patients were included in the study, and twenty were analyzed. The change from SP to PP significantly increased FRC (from 965 ± 397 to 1140 ± 490 ml, p = 0.008) and EELV (from 1566 ± 476 to 1832 ± 719 ml, p = 0.008), but PEEP-induced lung volume recruitment did not significantly change (269 ± 186 ml in SP to 324 ± 188 ml in PP, p = 0.263). Dynamic strain at PEEP decreased with the change from SP to PP (0.38 ± 0.14 to 0.33 ± 0.13, p = 0.040). As compared to supine, prone position increases resting lung volumes and decreases dynamic lung strain.


Dating the diversification of the major lineages of Passeriformes (Aves).
The avian Order Passeriformes is an enormously species-rich group, which comprises almost 60% of all living bird species. This diverse order is believed to have originated before the break-up of Gondwana in the late Cretaceous. However, previous molecular dating studies have relied heavily on the geological split between New Zealand and Antarctica, assumed to have occurred 85-82 Mya, for calibrating the molecular clock and might thus be circular in their argument. This study provides a time-scale for the evolution of the major clades of passerines using seven nuclear markers, five taxonomically well-determined passerine fossils, and an updated interpretation of the New Zealand split from Antarctica 85-52 Mya in a Bayesian relaxed-clock approach. We also assess how different interpretations of the New Zealand-Antarctica vicariance event influence our age estimates. Our results suggest that the diversification of Passeriformes began in the late Cretaceous or early Cenozoic. Removing the root calibration for the New Zealand-Antarctica vicariance event (85-52 Mya) dramatically increases the 95% credibility intervals and leads to unrealistically old age estimates. We assess the individual characteristics of the seven nuclear genes analyzed in our study. Our analyses provide estimates of divergence times for the major groups of passerines, which can be used as secondary calibration points in future molecular studies. Our analysis takes recent paleontological and geological findings into account and provides the best estimate of the passerine evolutionary time-scale currently available. This time-scale provides a temporal framework for further biogeographical, ecological, and co-evolutionary studies of the largest bird radiation, and adds to the growing support for a Cretaceous origin of Passeriformes.


Drug-induced hypothyroidism.
The thyroid axis is particularly prone to interactions with a wide variety of drugs, whose list increases year by year. Hypothyroidism is the most frequent consequence of drug-induced thyroid dysfunction. The main mechanisms involved in the development of primary hypothyroidism are: inhibition of the synthesis and/or release of thyroid hormones, immune mechanisms related to the use of interferon and other cytokines, and the induction of thyroiditis associated with the use of tyrosine kinase inhibitors and drugs blocking the receptors for vascular endothelial growth factor. Central hypothyroidism may be induced by inhibition of thyroid-stimulating hormone (bexarotene or corticosteroids) or by immunological mechanisms (anti-CTLA4 or anti-PD-1 antibody drugs). It is also important to recognize those drugs that generate hypothyroidism by interaction in its treatment, either by reducing the absorption or by altering the transport and metabolism of levothyroxine. Thus, it is strongly recommended to evaluate thyroid function prior to the prescription of medications such as amiodarone, lithium, or interferon, and the new biological therapies that show important interaction with thyroid and endocrine function in general.


Hutchinson-Gilford progeria syndrome: review of the phenotype.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.


Health of ophthalmologists as a prerequisite of quality medical services.
Introduction: The effectiveness and efficiency of the medical sector workforce directly depend on health of medical professionals. Scientific literature pays considerable attention to the health of surgeons, physicians, obstetricians, gynecologists, infectionists and dentists paying very little, if any, attention to health problems of ophthalmologists. This study is intended to bridge this gap. The aim at revealing the current situation and characteristics of health status of ophthalmologists using the results of sociological research and identifying health problems of the respondents in order to determine reliable preventive measures. Materials and methods: The authors used bibliographic, medical-statistical, sociological and informational-analytical methods as well as analyzed questionnaires of the sociological survey conducted among ophthalmologists from various regions of Ukraine. Results: The results of the sociological survey allowed determining the main medical-demographic and occupational characteristics of the ophthalmologists working at health facilities. It was found that11,1±2,1 per 100 respondents assess their health condition as very good and 34,3±3,2 per 100 respondents - as good. At the same time every third respondent reports own health condition as satisfactory, 18,5±2,6 per 100 respondents report their health condition as bad and 2,8±1,2 per 100 respondents - as very bad. Chronic diseases in the history were confirmed by 52,8±3,4 per 100 ophthalmologists, recurrent acute diseases were reported by 48,6±3,4 per 100 respondents. Some ophthalmologists reported their low medical activity due to a number of reasons. The main factors that adversely affect the health of ophthalmologists include considerable workload, the need to work part-time for subsistence, neuro-emotional stress, insufficiently equipped medical and diagnostic process lacking modern technologies, poor team atmosphere, lack of comfort at the workplace and others. Conclusions: Own health condition assessed by ophthalmologists, the prevalence of chronic and acute pathology, factors of the working environment affecting health serve as the ground for improving prophylaxis activities among ophthalmologists and strengthening their health as a prerequisite for the quality medical services.


Molecular cloning and characterization of a new basic peroxidase cDNA from soybean hypocotyls infected with Phytophthora sojae f.sp. glycines.
Differential display techniques were used to isolate cDNA clones corresponding to genes which were expressed in soybean hypocotyls by Phytophthora sojae f.sp. glycines infection. With a partial cDNA clone C20CI4 from the differential display PCR as a probe, a new basic peroxidase cDNA clone, designated GMIPER1, was isolated from a cDNA library of soybean hypocotyls infected with P. sojae f.sp. glycines. Sequence analysis revealed that the peroxidase clone encodes a mature protein of 35,813 Da with a putative signal peptide of 27 amino acids in its N-terminus. The amino acid sequence of the soybean peroxidase GMIPER1 is between 54-75% identical to other plant peroxidases including a soybean seed coat peroxidase. Southern blot analysis indicated that multiple copies of sequences related to GMIPER1 exist in the soybean genome. The mRNAs corresponding to the GMIPER1 cDNA accumulated predominantly in the soybean hypocotyls infected with the incompatible race of P. sojae f.sp. glycines, but were expressed at low levels in the compatible interaction. Soybean GMIPER1 mRNAs were not expressed in hypocotyls, leaves, stems, and roots of soybean seedlings. However, treatments with ethephon, salicylic acid or methyl jasmonate induced the accumulation of the GMIPER1 mRNAs in the different organs of soybean. These results suggest that the GMIPER1 gene encoding a putative pathogen-induced peroxidase may play an important role in induced resistance of soybean to P. sojae f.sp. glycines and in response to various external stresses.


Identification of blood biomarkers in glioblastoma by SWATH mass spectrometry and quantitative targeted absolute proteomics.
Molecular biomarkers in blood are needed to aid the early diagnosis and clinical assessment of glioblastoma (GBM). Here, in order to identify biomarker candidates in plasma of GBM patients, we performed quantitative comparisons of the plasma proteomes of GBM patients (n = 14) and healthy controls (n = 15) using SWATH mass spectrometry analysis. The results were validated by means of quantitative targeted absolute proteomics analysis. As a result, we identified eight biomarker candidates for GBM (leucine-rich alpha-2-glycoprotein (LRG1), complement component C9 (C9), C-reactive protein (CRP), alpha-1-antichymotrypsin (SERPINA3), apolipoprotein B-100 (APOB), gelsolin (GSN), Ig alpha-1 chain C region (IGHA1), and apolipoprotein A-IV (APOA4)). Among them, LRG1, C9, CRP, GSN, IGHA1, and APOA4 gave values of the area under the receiver operating characteristics curve of greater than 0.80. To investigate the relationships between the biomarker candidates and GBM biology, we examined correlations between plasma concentrations of biomarker candidates and clinical presentation (tumor size, progression-free survival time, or overall survival time) in GBM patients. The plasma concentrations of LRG1, CRP, and C9 showed significant positive correlations with tumor size (R2 = 0.534, 0.495, and 0.452, respectively).


Biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs as novel VEGFR2 inhibitors; Design, synthesis and anti-angiogenic activity.
Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as a vital tool for cancer treatment. In this study, a new series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized as novel VEGFR2 inhibitors. The biochemical profiles of the target compounds were investigated using viability of human umbilical vascular endothelial cells (HUVECs), migration assay and Western blot using sorafenib as reference antiangiogenic drug. Most of the tested compounds exhibited significant antiproliferative activity against HUVECs, where compounds 3a, 3e, 3g, 3h and 3l exhibited better antiproliferative activity than sorafenib. All compounds significantly inhibited VEGF stimulated migration of HUVECs at 10 µM dose with (3a, 3e, 3g, 3h and 3l) showing better or comparable inhibitory activities to that of sorafenib. Moreover, Western blotting analysis confirmed antiangiogenic effect of those compounds with significant reduction in the level of VEGFR-2 compared to sorafenib. Finally, cytotoxicity screening of these derivatives against four cancer cells and RPE1 as normal cell line was performed. The mechanistic effectiveness in cell cycle progression and apoptotic induction were evaluated for the promising compound 3e due to its remarkable cytotoxic activity against tested cancer cell lines and significant VEGFR-2 inhibition. Flow cytometric analysis showed that compound 3e induced cell growth arrest at G2/M phase and stimulated the apoptotic death of HepG2 cells.


Citrullinemia: prenatal diagnosis of an affected fetus.
We monitored a pregnancy in a family at risk for citrullinemia due to argininosuccinic acid (ASA) synthetase deficiency. ASA synthetase activity in cultured epithelioid amniotic fluid cells from the fetus at risk was less than 2% of control epithelioid amniotic fluid cell activity. An increased concentration of citrulline was found in the at-risk amniotic fluid (0.14 mumol/ml) as compared with fluid from six controls and one at-risk but unaffected pregnancy (trace). The pregnancy was terminated, and the in utero diagnosis was confirmed by assay of ASA synthetase activity in cultured fetal skin fibroblasts (4.4% of control activity). In addition, all five fetal tissues studied had significant accumulation of citrulline, whereas control fetal tissues had none. These data provide evidence that, if precise control is maintained over tissue culture variables, citrullinemia can be diagnosed successfully in utero by microassay of ASA synthetase activity in cultured amniotic fluid cells. They also suggest that amniotic fluid citrulline concentrations provide strong adjunctive evidence for this prenatal diagnosis.


Better recovery from lameness among dairy cows housed in hospital pens.
Housing in hospital pens may be beneficial for lame cows due to soft flooring and less competition for resources. We compared recovery from lameness among dairy cows housed in designated hospital pens, with deep-litter straw, with recovery among cows housed together with the rest of the lactating cows in their home pens, with cubicles and slatted or solid concrete floors. Additionally, we compared lying behavior in the 2 groups of cows. A total of 168 lame dairy cows from 5 herds were included in the study. Each herd was visited once weekly, and lame cows (locomotion score 3 or 4 on a 5-point scale) were examined in a hoof-trimming chute, trimmed, and randomly assigned to 1 of 2 treatments: housing in a hospital pen (termed "treatment"; 72 cows) or housing under the herds' standard conditions together with the rest of the lactating cows in the herd (termed "control"; 96 cows). Cows were locomotion scored weekly until they were no longer lame or until they had been part of the trial for 3 weeks (i.e., 2, 3, or 4 locomotion scorings per cow). We categorized cows to describe the progression of lameness over time: recovery (divided into fast, medium, or slow), improvement without recovery, constant lameness, or worsening of lameness. Lying behavior was recorded in a sample of 60 of the 168 cows for a period of 5 d. Overall, recovery from lameness was significantly different between treatment and control cows. The proportion of cows included in the study with locomotion score 4 and a subsequent improvement was significantly higher among treatment cows than among control cows. Among cows included with locomotion score 4, 40% of treatment cows also had a locomotion score 4 at the fourth locomotion scoring, 46% had improved to a score 3, and 14% were no longer lame. In comparison, 73% of control cows had a locomotion score 4 at the fourth locomotion scoring, 16% had improved to a score 3, and 11% were no longer lame. We found no differences between treatment and control cows for mean daily lying time, number of steps per day, number of daily lying bouts, or mean duration of lying bouts. Housing of lame dairy cows in a hospital pen with a soft surface, easier access to feed and water, a smaller group size, and reduced waiting time for milking may have positive effects on recovery from lameness. Typically, farmers have housed only severely lame cows in hospital pens. However, our results indicate that less severely lame cows may also benefit from a stay in a hospital pen.


Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance Epidemiology and End Results database analysis.
To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi-square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer-specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes compared to patients with isolated lung or distant nodal metastases. Further research is needed to identify the highly selected subset of patients who may benefit from local treatment of the primary tumor and/or metastatic disease.


Induction of lymphomas by inoculation of Marek's disease virus-derived lymphoblastoid cell lines: prevention by CVI988 vaccination.
Lymphoblastoid cell lines 265(L) and 990(O) are monoclonal lymphomas, derived respectively from liver and ovarian tumours, generated in inbred P-line (MHC B(19)/B(19)) chickens infected with RB-1B strain of Marek's disease virus (MDV) and pRB-1B5 BAC clone respectively. These were inoculated into inbred, MDV-susceptible, P-line chickens by intra-venous or intra-abdominal routes. Additional groups of birds were vaccinated using 1000 plaque-forming units of CVI988 vaccine 8 days prior to inoculation of the cell lines. Non-vaccinated birds developed visceral Marek's disease tumours with an increased rate 30 to 60 days post inoculation. Vaccination prevented tumour and disease development in challenged birds. TCRβ repertoire analysis by spectratyping and sequencing of the inoculum was used to track tumour identity in primary tumours and tumour cell lines derived from inoculated birds. These data revealed that the tumours were a consequence of de novo virus infection and not metastasis and expansion of the inoculated tumour cells. Moreover, the data showed that the two MDV-derived cell lines were not transplantable even in syngeneic P-line birds. The data also demonstrated the application of spectratyping as a tool to track tumour identity in lymphoma transplantation studies.


Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity.
Stress facilitates reinstatement of addictive drug seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTPGABA), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTPGABA. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTPGABA. Using a kappa receptor antagonist as a selective tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.


Persistent airway hyper-responsiveness and inflammation in Toxocara canis-infected BALB/c mice.
Infection with Toxocara canis, the roundworm of dogs, has been associated with asthmatic manifestations. Clinical symptoms such as wheezing, coughing and episodic airflow obstruction have been described for patients infected with this helminth. In order to characterize the effect of T. canis infection on the lungs, we monitored immune responses, pulmonary pathology and lung function over a period of 60 days in BALB/c mice. Infection was performed by a single oral administration of 1000 T. canis embryonated eggs. Airway responsiveness was measured in conscious, unrestrained mice at 7, 14, 30 and 60 days post-infection (p.i.). Infection of mice resulted in airway hyper-responsiveness (AHR) that persisted up to 30 days p.i. Pulmonary inflammation as well as increased levels of IgE and eosinophils in bronchoalveolar lavage (BAL) persisted up to 60 days p.i. Cytokine analysis in BAL indicated increased levels of IL-5 at day 7 and 14 p.i., whereas the levels of IL-2, IFN-gamma, IL-4 and IL-10 did not differ from those of uninfected controls. Toxocara-specific stimulation of spleen cells using recombinant TES-70 protein resulted in the induction of IL-5 at day 7 and 14 p.i. and IL-10 at day 14 p.i. Production of all other cytokines did not differ from that of uninfected controls. Evaluation of larval burden revealed that T. canis was still present in the lungs of infected mice at 60 days p.i. The presence of Toxocara larva in the lungs at 60 days p.i. following a single infection could explain the persistent pulmonary inflammation, airway hyper-reactivity, eosinophilia and increased IgE production observed in T. canis-infected BALB/c mice.


Endonuclease cleavage of blocked replication forks: An indirect pathway of DNA damage from antitumor drug-topoisomerase complexes.
The cytotoxicity of several important antitumor drugs depends on formation of the covalent topoisomerase-DNA cleavage complex. However, cellular processes such as DNA replication are necessary to convert the cleavage complex into a cytotoxic lesion, but the molecular mechanism of this conversion and the precise nature of the cytotoxic lesion are unknown. Using a bacteriophage T4 model system, we have previously shown that antitumor drug-induced cleavage complexes block replication forks in vivo. In this report, we show that these blocked forks can be cleaved by T4 endonuclease VII to create overt DNA breaks. The accumulation of blocked forks increased in endonuclease VII-deficient infections, suggesting that endonuclease cleavage contributes to fork processing in vivo. Furthermore, purified endonuclease VII cleaved the blocked forks in vitro close to the branch points. These results suggest that an indirect pathway of branched-DNA cleavage contributes to the cytotoxicity of antitumor drugs that target DNA topoisomerases.


Genetic neuropathology of Parkinson's disease.
Parkinson's disease (PD) has long been considered to be a sporadic entity, perhaps with an environmental etiology. However, recent genetic discoveries have challenged this view, as there are many families with diseases of Mendelian inheritance that clinically resemble PD. Here, we will review in detail the neuropathological data relating to familial cases of PD. We will discuss the complicated relationships between the genetically defined cases and the two key pathological events seen in PD, namely loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of protein inclusions, Lewy bodies, in the neurons that survive to the end stage of the disease course. These observations will be synthesized into an overall scheme that emphasizes the two key aspects of the neuropathology as distinct events and suggest that each gene tells us something a little different about the neuropathology of PD.


Cox-sMBPLS: An Algorithm for Disease Survival Prediction and Multi-Omics Module Discovery Incorporating Cis-Regulatory Quantitative Effects.
The development of high-throughput techniques has enabled profiling a large number of biomolecules across a number of molecular compartments. The challenge then becomes to integrate such multimodal Omics data to gain insights into biological processes and disease onset and progression mechanisms. Further, given the high dimensionality of such data, incorporating prior biological information on interactions between molecular compartments when developing statistical models for data integration is beneficial, especially in settings involving a small number of samples. We develop a supervised model for time to event data (e.g., death, biochemical recurrence) that simultaneously accounts for redundant information within Omics profiles and leverages prior biological associations between them through a multi-block PLS framework. The interactions between data from different molecular compartments (e.g., epigenome, transcriptome, methylome, etc.) were captured by using cis-regulatory quantitative effects in the proposed model. The model, coined Cox-sMBPLS, exhibits superior prediction performance and improved feature selection based on both simulation studies and analysis of data from heart failure patients. The proposed supervised Cox-sMBPLS model can effectively incorporate prior biological information in the survival prediction system, leading to improved prediction performance and feature selection. It also enables the identification of multi-Omics modules of biomolecules that impact the patients' survival probability and also provides insights into potential relevant risk factors that merit further investigation.


Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca(2+)-mobilizing second messenger. Structure--activity relationship of the N1-ribose moiety.
We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cADPR, which were the 2"-deoxy analogue 3, the 3"-deoxy analogue 4, the 3"-deoxy-2"-O-(methoxymethyl) analogue 5, the 3"-O-methyl analogue 6, the 2",3"-dideoxy analogue 7, and the 2",3"-dideoxydidehydro analogue 8, were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates. We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation. The Ca(2+)-mobilizing effects were evaluated systematically using three different biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes. The relative potency of Ca(2+)-mobilization by these cADPR analogues varies depending on the cell-type used: e.g., 3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) >> cADPcR (2) approximately 3"-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-type selective cADPR analogues, which can be used as biological tools and/or novel drug leads.


Assessing Microbial Metabolic and Biological Diversity to Inform Natural Product Library Assembly.
The pressing need for novel chemical matter to support bioactive compound discovery has led natural product researchers to explore a wide range of source organisms and environments. One of the implicit guiding principles behind those efforts is the notion that sampling different environments is critical to accessing unique natural products. This idea was tested by comparing fungi from disparate biomes: aquatic sediments from Lake Michigan (USA) and terrestrial samples taken from the surrounding soils. Matched sets of Penicillium brevicompactum, Penicillium expansum, and Penicillium oxalicum from the two source environments were compared, revealing modest differences in physiological performance and chemical output. Analysis of LC-MS/MS-derived molecular feature data showed no source-dependent differences in chemical richness. High levels of scaffold homogeneity were also observed with 78-83% of scaffolds shared among the terrestrial and aquatic Penicillium spp. isolates. A comparison of the culturable fungi from the two biomes indicated that certain genera were more strongly associated with aquatic sediments (e.g., Trichoderma, Pseudeurotium, Cladosporium, and Preussia) versus the surrounding terrestrial environment (e.g., Fusarium, Pseudogymnoascus, Humicola, and Acremonium). Taken together, these results suggest that focusing efforts on sampling the microbial resources that are unique to an environment may have a more pronounced effect on enhancing the sought-after natural product diversity needed for chemical discovery and screening collections.


Patient and Care Team Perspectives of Telemedicine in Critical Access Hospitals.
Telemedicine acute care may address issues facing critical access hospitals. This evaluation used web, mail, and telephone surveys to quantitatively and qualitatively assess patient and care team experience with telemedicine in 3 rural critical access hospitals and a large metropolitan tertiary care hospital. Results show that patients, nurses, and clinicians perceived quality of care as high, and they offered feasible recommendations to enhance communication and otherwise improve the experience. Continued work to improve, test, and publish findings on patient and care team experience with telemedicine is critical to providing quality services in often underserved communities.


Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years.
Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas sharing common translocations whose natural history are not well known. We report on the nationwide exhaustive series of 330 patients with SEF or LGFMS in NETSARC+ since 2010. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB). Since 2010, (i) pathological review has been mandatory for sarcoma,and (ii) tumour/patients' characteristics have been collected in the NETSARC+ nationwide database. The characteristics of patients with SEF and LGFMS and their outcome are compared. 35/73 (48%) and 125/257(49%) of patients with SEF and LGFMS were female. More visceral, bone and trunk primary sites were observed in SEF (p < 0.001). 30% of SEF vs 4% of LGFMS patients had metastasis at diagnosis (p < 0.0001). Median size of the primary tumor was 51 mm (range 10-90) for LGFMS vs 80 (20-320) for SEF (p < 0.001). Median age for LGFMS patients was 12 years younger than that of SEF patients (43 [range 4-98] vs 55 [range 10-91], p < 0.001). Neoadjuvant treatment was more often given to SEF (16% vs 9%, p = 0.05). More patients with LGFMS were operated first in reference centers (51% vs 26%, p < 0.001). The R0 rate on the operative specimen was 41% in LGFMS vs 16% in SEF (p < 0.001). Median event-free survival (EFS) of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median overall survival (OS) was not reached. Fifty-months OS was 93% vs 81% for LGFMS vs SEF (p = 0.05). Median OS was 77 months after first relapse, similar for SEF and LGFMS. In multivariate analysis, age, tumor size, metastasis at diagnosis were independent prognostic factors for OS in LGFMS. Although sharing close molecular alterations, SEF and LGFMS have a different natural history, clinical presentation and outcome, with a higher risk of metastatic relapse in SEF. Survival after relapse is longer than with other sarcomas, and similar for SEF and LGFMS.


Endoscopic diverticulotomy for the treatment of Zenker's diverticulum: results in 102 patients with staple-assisted endoscopy.
Endoscopic diverticulotomy for the treatment of Zenker's diverticulum has been reported infrequently in the literature and has engendered considerable controversy. Between March 1992 and September 1996, we attempted to treat 102 patients with endoscopic treatment for pharyngoesophageal diverticula. In 98 patients, the endoscopic surgery was successfully completed. Conversion to open surgery was required in 4 patients (3.92%). One cartridge of staples in 16 patients (16.32%), 2 cartridges in 78 patients (79.59%), and 3 cartridges in 4 patients (4.08%) were used, according to the size of the diverticulum; the median duration of the procedure was 20 minutes (10 to 60 minutes). No postoperative morbidity or mortality was recorded. Oral feeding was started following radiologic control after a median of 2 days; the median hospital stay was 4 days. The median follow-up is 16 months (1 to 45 months). Four patients operated on before the introduction of the modified stapler showed a persistent diverticular pouch: 3 underwent repeat endoscopic operation, and 1 underwent conventional open surgery. All treated patients are asymptomatic. Manometric study performed in 15 patients showed a significant reduction of basal upper esophageal sphincter pressure compared to preoperative data (48.30+/-21.74 versus 29.38+/-5.68 mm Hg; p<.01). We therefore recommend endoscopic diverticulotomy, considering that the procedure is relatively safe and effective, with minimal patient discomfort, and the results are equal to those of the external approach. This procedure offers the advantages of short hospitalization, rapid convalescence, brief operative time, absence of skin incision. predictable resolution of symptoms, and reduced morbidity.


Hemodynamic and autonomic changes in adults with obstructive sleep apnea.
Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airway during sleep that lead to an increase in airway resistance and respiratory effort. This may produce oxygen desaturation, hypercapnia and central nervous system arousal that restore airflow. OSA is associated with hemodynamic changes that are related to alterations in the activity of the autonomic nervous system. During the course of an apnea, the heart rate may slow down, increase or remain stable. The blood pressure decreases at the start of the apnea and increases at its terminal portion. When ventilation resumes, heart rate, blood pressure and ventilation reach a peak accompanied by an abrupt reduction in left ventricular stroke volume. During the early phase of apnea, sympathetic nerve activity (SNA) is suppressed; it then increases constantly and reaches a peak at the end of apnea and on arousal. As soon as ventilation resumes, there is an abrupt inhibition of SNA in the peripheral blood vessels. The resumption of ventilation occurs in the context of peripheral vasoconstriction and increased peripheral resistance. This situation persists for several seconds after the SNA has ceased, due to the kinetics of norepinephrine uptake, release and washout at the neurovascular junction. Hypoxemia, hypercapnia, lung inflation and blood pressure are important factors that may modulate these autonomic changes. The alterations in the autonomic nervous system are carried over into wakefulness and may contribute to the development of the cardiovascular disorders associated with OSA, including sympathovagal imbalance accompanied with changes in the baroreflex and chemoreflex. The hemodynamic and autonomic dysfunction associated with OSA is improved following treatment with continuous positive airway pressure.


[Functional childhood gastrointestinal disorders. II. Constipation and solitary encopresis: physiology and pathophysiology].
The childhood prevalences of constipation and encopresis are 0.3-8% and 1-3% respectively. Following a recent stricter definition and classification, constipation and solitary encopresis are now recognised to be two separate entities. Constipation is characterised by infrequent defecation, often in combination with involuntary loss of faeces. Solitary encopresis most often occurs once a day after school hours. When there is no defecation, the frequency of encopresis increases, the abdominal pain becomes more severe and the appetite becomes less, until a large quantity of faeces is produced (often once per week). The physiology of the defecation and continence mechanism is complex and has only been unravelled in part. The multiple physiological mechanisms involved have a complementary and compensatory effect on each other. This makes it difficult to determine the underlying pathophysiological mechanisms of these functional disorders.


The Effect of Frailty versus Initial Glasgow Coma Score in Predicting Outcomes Following Chronic Subdural Hemorrhage: A Preliminary Analysis.
Background Initial Glasgow Coma Score (iGCS) is a well-known predictor of adverse outcomes following chronic subdural hemorrhage (cSDH). Frailty, i.e. a reduced physiologic reserve, is associated with poorer outcomes across the surgical literature, however, there is no consensus on the best measure of frailty. To date, no study has compared frailty's ability to predict cSDH outcomes versus iGCS. The goal of this study was to, therefore, examine the prognostic value of the 5- (mFI-5) and 11-factor (mFI-11) modified frailty index, and Charlson Comorbidity Index (CCI) versus iGCS following cSDH. Methods Between January, 2016 and June, 2018, patients who presented to the emergency department with cSDH were retrospectively identified using the International Classification of Diseases (ICD) codes. mFI-5, mFI-11, and CCI scores were calculated using patient baseline characteristics. Primary endpoints were death and discharge home and subgroup analyses were performed among operative cSDH. Univariate and multivariate logistic regressions were used to determine predictors of primary endpoints. Results Of the 109 patients identified, the average age was 72.6±1.6 years and the majority (69/109, 63.3%) were male. The average CCI, mFI-5, and mFI-11 were 4.5 ±0.2, 1.5 ±0.1, and 2.2 ±0.1, respectively. Fifty (45.9%) patients required surgical intervention, 11 (10.1%) died, and 48 (43.4%) were discharged home. In the overall cohort, while the only multivariate predictor of mortality was iGCS (OR=0.58; 95%CI:0.44-0.77; p=0.0001), the CCI (OR=0.73; 95%CI:0.58-0.92; p=0.0082) was a superior predictor of discharge home compared to iGCS (OR=1.46; 95%CI:1.13-1.90; p=0.0041). Conversely, among those who received an operative intervention, the CCI, but not iGCS, independently predicted both mortality (OR=4.24; 95%CI:1.01-17.86; p=0.0491) and discharge home (OR=0.55; 95%CI:0.33-0.90; p=0.0170). Neither mFI nor age predicted primary outcomes in multivariate analysis. Conclusion While frailty is associated with worse surgical outcomes, the clinical utility of the mFI-5, mFI-11, and CCI in cSDH is unclear. We show that the iGCS is an overall superior predictor of mortality following cSDH but is outperformed by the CCI after operative intervention. Similarly, the CCI is the superior predictor of discharge home in cSDH patients overall and following an operative intervention. These results indicate that while the iGCS best predicts mortality overall, the CCI may be considered when prognosticating post-operative course and hospital disposition.


Livestock veterinarians at high risk of acquiring methicillin-resistant Staphylococcus aureus ST398.
The prevalence and risk factors associated with livestock-associated MRSA (LA-MRSA) carriage was examined in Danish and Belgian veterinarians. The MRSA and LA-MRSA carriage rates were 9·5% (95% CI 5·3-15·6) and 7·5% (95% CI 3·8-13·1) for MRSA and LA-MRSA, respectively, in Belgium and 1·4% (95% CI: 0·17-5·05) in Denmark (all Danish MRSA isolates belonged to the LA-MRSA genotype). All LA-MRSA isolates were resistant to tetracycline and 53·4% (7/13) showed a multi-resistant phenotype. LA-MRSA was significantly associated with veterinarians in contact with livestock (P=0·046). In the multivariable analysis, working with small animals in a veterinary clinic seems to be negatively associated (OR 0·15, 95% CI 0-1·0, P=0·05) and a strong direct association was found for LA-MRSA acquisition and exposure to live pigs (OR 12·1, 95% CI 1·6-548·5, P=0·01). Since carriage of MRSA ST398 may increase the risk of complications during hospitalization, our results underline that preventive measures may need to be developed for veterinary professionals, particularly for livestock veterinarians.


Evaluation of polymethyl-methacrylate and acetal denture base resins processed by two different techniques before and after nano-chlorohexidine surface treatment.
Flexible denture base polymers have gained popularity in modern dentistry however, their biofilm formation tendency, adversely affecting the oral tissue heath, remains a concern. Consequently, this study aimed to evaluate surface roughness and biofilm formation tendency of two types of denture base resins manufactured with two techniques before and after surface coating with chlorohexidine (CHX) NPs. Acetal (AC) and Polymethyl-methacrylate (PMMA) resins manufactured by conventional and CAD/CAM methods were shaped into disk (10 X 10 X 1 mm). They were dipped for 8 h and 24 h in colloidal suspension prepared by mixing aqueous solution of CHX digluconate and hexa-metaphosphate (0.01 M). Surface roughness, optical density (OD) of microbial growth media and biofilm formation tendency were evaluated directly after coating. Elutes concentrations of released CHX were evaluated for 19 days using spectrophotometer. Three-way ANOVA and Tukey's post-hoc statistical analysis were used to assess the outcomes. AC CAD/CAM groups showed statistically significant higher roughness before and after coating (54.703 ± 4.32 and 77.58 ± 6.07 nm, respectively). All groups showed significant reduction in OD and biofilm formation tendency after surface coating even after 19 days of CHX NPs release. Biofilm formation tendency was highly relevant to surface roughness of tested resins before coating. After CHX NPs coating all tested groups showed significant impact on microbial growth and reduction in biofilm formation tendency with no relation to surface roughness. Significant antimicrobial effect remained even after 19 days of NPs release and specimens storage.


ReaxFF Parameter Optimization with Monte-Carlo and Evolutionary Algorithms: Guidelines and Insights.
ReaxFF is a computationally efficient force field to simulate complex reactive dynamics in extended molecular models with diverse chemistries, if reliable force-field parameters are available for the chemistry of interest. If not, they must be optimized by minimizing the error ReaxFF makes on a relevant training set. Because this optimization is far from trivial, many methods, in particular, genetic algorithms (GAs), have been developed to search for the global optimum in parameter space. Recently, two alternative parameter calibration techniques were proposed, that is, Monte-Carlo force field optimizer (MCFF) and covariance matrix adaptation evolutionary strategy (CMA-ES). In this work, CMA-ES, MCFF, and a GA method (OGOLEM) are systematically compared using three training sets from the literature. By repeating optimizations with different random seeds and initial parameter guesses, it is shown that a single optimization run with any of these methods should not be trusted blindly: nonreproducible, poor or premature convergence is a common deficiency. GA shows the smallest risk of getting trapped into a local minimum, whereas CMA-ES is capable of reaching the lowest errors for two-third of the cases, although not systematically. For each method, we provide reasonable default settings, and our analysis offers useful guidelines for their usage in future work. An important side effect impairing parameter optimization is numerical noise. A detailed analysis reveals that it can be reduced, for example, by using exclusively unambiguous geometry optimization in the training set. Even without this noise, many distinct near-optimal parameter vectors can be found, which opens new avenues for improving the training set and detecting overfitting artifacts.


Rotational Thromboelastometry Profile in Children With Chronic Spontaneous Urticaria.
The pathogenesis of chronic spontaneous urticaria (CSU) is incompletely understood. There is a growing interest in the role of the coagulation cascade in chronic urticaria. Rotational thromboelastometry (ROTEM) assay enables the global assessment of coagulation status. In the present study, we aimed to test the coagulation profile in children with CSU using ROTEM and correlate these parameters with those of a healthy group. A total of 24 children with active CSU (11 girls and 13 boys) 8 to 17 years of age and age-matched and sex-matched 30 healthy control participants were enrolled in the study. ROTEM assays (intrinsic thromboelastometry and extrinsic thromboelastometry) were used to measure and analyze coagulation time, clot formation time, and maximum clot firmness. The CSU patients and controls did not differ in age, sex, erythrocyte, neutrophil, and platelet counts. Also, ROTEM parameters did not show any difference between the 2 groups. ROTEM is increasingly being used as a tool for monitoring coagulation status. In this study, ROTEM parameters did not show any difference between CSU patients and the healthy group. Further studies are needed to confirm our findings on a larger number of CSU patients.


ELM: enhanced lowest common ancestor based method for detecting a pathogenic virus from a large sequence dataset.
Emerging viral diseases, most of which are caused by the transmission of viruses from animals to humans, pose a threat to public health. Discovering pathogenic viruses through surveillance is the key to preparedness for this potential threat. Next generation sequencing (NGS) helps us to identify viruses without the design of a specific PCR primer. The major task in NGS data analysis is taxonomic identification for vast numbers of sequences. However, taxonomic identification via a BLAST search against all the known sequences is a computational bottleneck. Here we propose an enhanced lowest-common-ancestor based method (ELM) to effectively identify viruses from massive sequence data. To reduce the computational cost, ELM uses a customized database composed only of viral sequences for the BLAST search. At the same time, ELM adopts a novel criterion to suppress the rise in false positive assignments caused by the small database. As a result, identification by ELM is more than 1,000 times faster than the conventional methods without loss of accuracy. We anticipate that ELM will contribute to direct diagnosis of viral infections. The web server and the customized viral database are freely available at http://bioinformatics.czc.hokudai.ac.jp/ELM/.


Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria.
In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% white) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999, through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. The mean size of gastric adenocarcinomas was 23.0 ± 16.6 mm-most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI, 1.4-10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8-12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases.


[Multi-media computer-based chart: modern tool of clinical record keeping].
To design the program of computer multimedia case history (MCH) for collection, storage and analysis of information about the patient including diagnostic images; to test MCH for application in telemedical consulting and control over valid conduction of the treatment protocol. Brief representation of information is reached by integrated multilevel placement of the data on common time axis. Dynamics of the selected parameters is represented as normalized diagrams in the same system axes. Electron tables are filled either by hand or import of the data from individual electron file of all the information about the patient. Diagnostic images and conclusions are obtained from local computer bases of the diagnostic units. Inexpensive commonly used computers allows one to input digital micro- and macrophotos, x-ray images, etc. Monitor information is available from the universal computer net directly from the monitors Geolink-M. MCH was tested in the Hematological Research Center of RAMS. In cooperation with Bryansk diagnostic center N 1 telemedical consulting and some data bases were perfected. The MCH system joints routine activity of the clinic without any problems raising quality of the patients management, facilitating the access to therapeutic and diagnostic information and its analysis. On-line breaking the limits of the controlled parameters and protocols is detected automatically. These events are emphasized by "blocking questions" which must be worked out by the user. The information on the patient can be fully stored on CD-ROM in line with the MCH program providing organization of the data. The system is introduced which collects medical information from various sourses and builds up comprehensive representation of the data on the same time axis. The system provides control over implimintation of the protocols of the patients' management, gives a convenient access to medical information, ensures its reliable storage and availability in case of the patients transfer to other medical institutions, facilitates analysis of clinical cases, conduction of medical consulting.


Association of baseline and dynamic arterial stiffness status with dyslipidemia: a cohort study.
Dyslipidemia is known to contribute to arterial stiffness, while the inverse association remains unknown. This study aimed to explore the association of baseline arterial stiffness and its changes, as determined by brachial-ankle pulse wave velocity (baPWV), with dyslipidemia onset in the general population. This study enrolled participants from Beijing Health Management Cohort using measurements of the first visit from 2012 to 2013 as baseline, and followed until the dyslipidemia onset or the end of 2019. Unadjusted and adjusted Cox proportional regression models were used to evaluate the associations of baseline baPWV and baPWV transition (persistent low, onset, remitted and persistent high) with incident dyslipidemia. Of 4362 individuals (mean age: 55.5 years), 1490 (34.2%) developed dyslipidemia during a median follow-up of 5.9 years. After adjusting for potential confounders, participants with elevated arterial stiffness at baseline had an increased risk of dyslipidemia (HR, 1.194; 95% CI, 1.050-1.358). Compared with persistent low baPWV, new-onset and persistent high baPWV were associated with a 51.2% and 37.1% excess risk of dyslipidemia. The findings indicated that arterial stiffness is an early risk factor of dyslipidemia, suggesting a bidirectional association between arterial stiffness and lipid metabolism.


Does a digoxin-like substance participate in vascular and pressure control during dietary sodium changes in patients with primary aldosteronism?
To evaluate the importance of an endogenous sodium pump inhibitor in the pathogenesis of low renin human hypertension, the urinary excretion of a digoxin-like immunoreactive substance (DLIS) was measured in eight patients with primary aldosteronism (n = 5, with adenomas) during two sequential 1-week periods of low- (20 mmol/l NaCl) and high- (200 mmol/l NaCl) sodium intake. DLIS excretion increased consistently during high-sodium intake while urinary aldosterone, plasma renin activity, cortisol and adrenocorticotropic hormone did not change. Although blood pressure showed a time-course parallel to that of the urinary DLIS, the blood pressure increments were not accompanied by evidence of vasoconstriction since forearm blood flow (plethysmographic technique) increased and forearm vascular resistances were reduced. Moreover, the reactivity of forearm arterioles to local norepinephrine was unchanged during the period of low- and high-salt intake, despite the fact that an endogenous sodium pump inhibitor should, supposedly, sensitize the responses to an adrenergic agonist. Finally, forearm vasoconstrictor responses to ouabain, a pharmacological Na+,K(+)-ATPase antagonist, were potentiated during the high-salt diet, a result not expected if an increased number of sodium pumps were occupied by an endogenous inhibitor. These results provide unequivocal evidence for a modulation by salt intake of the urinary excretion of a DLIS in patients with primary aldosteronism. This substance might participate in the regulation of body fluid volume in this syndrome and possibly in other physiological conditions. However, no evidence could be found for a cause--effect relationship between blood pressure and DLIS increments during high-salt intake, at least during the short-term course of the study.


Heat shock in Bacillus subtilis: genetic characterization of a mutant.
Bacillus subtilis strain BUL786, a transposon-generated mutant, lacks a 97 kD protein following heat shock and has unique protein secretion properties. In this study, transduction analysis demonstrated that the properties of high temperature protease secretion, heat shock protein distribution, and loss of the 97 kD heat shock protein were all transferred as a single trait to recipient bacteria. The high temperature-specific protease released by this mutant into the supernatant was also shown to be produced during heat shock by the parental cells, but is retained intracellularly.


Complex band structure of one-dimensional polariton crystal.
The exceptional point (EP), at which the relevant eigenvalues and eigenstates are simultaneously identical, typically exists in non-Hermitian systems with parity-time (PT) symmetric complex potentials, and gives rise to many intriguing behaviors in various physical realms. In this work, we explore the complex band structure of one-dimensional "polariton crystals" that can be constructed in waveguide-resonator coupled systems, with PT-symmetric potential. Analysis based on the transfer matrix and the coupled mode theory shows that the complex band structure is intimately determined by the interaction between the Bragg resonance and the polariton one, the gain/loss coefficients, in addition to the coupling strength. A miniband is induced due to the interaction of these two resonances, which is a defect-like band and appears quite different for the band structure evolution. Furthermore, PT-symmetric phase transition occurs in the momentum space for certain amounts of non-Hermiticity. As the non-Hermiticity increases, the EP formed in the original polariton gap approaches another EP formed at the touch point of the folded Bragg bands (where the thresholdless transition occurs). Then they coalesce at a specific non-Hermiticity, and finally disappear. Subsequently, the transmission spectra of such polariton crystals show intriguing phenomena induced by the EPs. Our results provide a different perspective to understand PT-symmetric polariton crystals and may find applications in gain/loss induced lasing by 'polaritons'.


Retrograde autologous priming in cardiac surgery: a systematic review and meta-analysis.
Guidelines recommend retrograde autologous priming (RAP) of the cardiopulmonary bypass circuit. However, the efficacy and safety of RAP is not well-established. We performed a systematic review and meta-analysis to determine the effects of RAP on transfusion requirements, morbidity and mortality. We searched Cochrane Central Register of Controlled Trials, Medline, ScienceDirect, Cumulative Index to Nursing and Allied Health Literature and Embase for randomized controlled trials (RCTs) and observational studies comparing RAP to no-RAP. We performed title and abstract review, full-text screening, data extraction and risk of bias assessment independently and in duplicate. We pooled data using a random effects model. Twelve RCTs (n = 1206) and 17 observational studies (n = 3565) were included. Fewer patients required blood transfusions with RAP [RCTs; risk ratio 0.58 [95% confidence interval (CI): 0.51, 0.65], P < 0.001, and observational studies; risk ratio 0.65 [95% CI: 0.53, 0.80], P < 0.001]. The number of units transfused per patient was also lower among patients who underwent RAP (RCTs; mean difference -0.38 unit [95% CI: -0.72, -0.04], P = 0.03, and observational studies; mean difference -1.03 unit [95% CI: -1.76, -0.29], P < 0.006). This meta-analysis supports the use of RAP as a blood conservation strategy since its use during cardiopulmonary bypass appears to reduce transfusion requirements.


Peer review of the quality of care. Reliability and sources of variability for outcome and process assessments.
Peer assessments have traditionally been used to judge the quality of care, but a major drawback has been poor interrater reliability. To compare the interrater reliability for outcome and process assessments in a population of frail older adults and to identify systematic sources of variability that contribute to poor reliability. Eight sites participating in a managed care program that integrates acute and long-term care for frail older adults. A total of 313 frail older adults. Retrospective review of the medical record with 180 charts randomly assigned to 2 geriatricians, 2 geriatric nurse practitioners, or 1 geriatrician and 1 geriatric nurse practitioner and 133 charts randomly assigned to either a geriatrician or a geriatric nurse practitioner. Interrater reliabilities for structured implicit judgments about process and outcomes for overall care and care for each of 8 tracer conditions (eg, arthritis). Outcome measures had higher interrater reliability than process measures. Five outcome measures achieved fair to good reliability (more than 0.40), while none of the process measures achieved reliabilities more than 0.40. Three factors contributed to poorer reliabilities for process measures: (1) an inability of reviewers to differentiate among cases with respect to the quality of management, (2) systematic bias from individual reviewers, and (3) systematic bias related to the professional training of the reviewer (ie, physician or nurse practitioner). Peer assessments can play an important role in characterizing the quality of care for complex patients with multiple interrelated chronic conditions, but reliability can be poor. Strategies to achieve adequate reliability for these assessments should be applied. These strategies include emphasizing outcomes measurement, providing more structured assessments to identify true differences in patient management, adjusting systematic bias resulting from the individual reviewer and their professional background, and averaging scores from multiple reviewers. Future research on the reliability of peer assessments should focus on improving the ability of process measures to differentiate among cases with respect to the quality of management and on identifying additional sources of systematic bias for both process and outcome measures. Explicit recognition of factors influencing reliability will strengthen efforts to develop sound measures for quality assurance.


Surgical treatment of medial epicondylitis. Results in 35 elbows.
We reviewed 35 of 38 consecutive patients who had operative treatment for medial epicondylitis of the elbow after the failure of conservative management. Their mean age was 43 years and mean follow-up was 85 months. At operation residual tears with incomplete healing were consistently found in the flexor origin at the medial epicondyle and microscopy showed reactive fibrous connective tissue with varying degrees of inflammation. The mean subjective estimate of elbow function was improved from 38% to 98% of normal, while isokinetic and grip strength testing in 16 patients showed no significant difference from the unoperated elbow. Results were excellent in 25 cases, good in nine and fair in one; 86% of the patients had no limitation in the use of the elbow.


Comparison of three instruments in predicting accidental falls in selected inpatients in a general teaching hospital.
Accidental patient falls are becoming a major cause of concern for hospitalized inpatients. It is well known that patients who fall once during their hospital stay are more likely to fall again and that fall rates tend to be higher in hospitalized elderly individuals. Concerned health care team personnel recognize that many accidental patient falls may be predicted and, thus, prevented. The best tool to predict falls has not been determined yet. The purpose of this study was to compare the abilities of the Morse Fall Scale (MFS), the Functional Reach (FR) test, and the nurses' clinical judgment in predicting those inpatients on a rehabilitation unit and a geriatric medical ward who were most likely to fall. A total of 98 patients were screened in a 3-month period, with each patient undergoing all three instruments the same day. The results showed that the two objective standardized tests (i.e., MFS, FR) were time consuming and often inconvenient and were no better at prediction than the clinical judgments made by the primary nurses.


Control of convective dissolution by chemical reactions: general classification and application to CO(2) dissolution in reactive aqueous solutions.
In partially miscible two-layer systems within a gravity field, buoyancy-driven convective motions can appear when one phase dissolves with a finite solubility into the other one. We investigate the influence of chemical reactions on such convective dissolution by a linear stability analysis of a reaction-diffusion-convection model. We show theoretically that a chemical reaction can either enhance or decrease the onset time of the convection, depending on the type of density profile building up in time in the reactive solution. We classify the stabilizing and destabilizing scenarios in a parameter space spanned by the solutal Rayleigh numbers. As an example, we experimentally demonstrate the possibility to enhance the convective dissolution of gaseous CO_{2} in aqueous solutions by a classical acid-base reaction.


In vitro evaluation of biocompatibility of Ti-Mo-Sn-Zr superelastic alloy.
Shape memory alloys (SMAs) including superelastic alloys have unique properties such as shape memory and superelasticity, thus they are recognized as very useful biomaterials. These properties are very advantageous for medical use, and actually the SMA wires have been widely used in medical field. However, biocompatibility of nickel-titanium (Ni-Ti) alloy, which is the only practical SMA at present, has been questioned because of its high nickel content. The aim of this study was to evaluate the biocompatibility of a newly developed Ni-free Ti-based SMA for medical use. The newly developed SMA made of Ti-Mo-Sn-Zr system was processed into a disk of 15.1 mm in diameter. Pure titanium of the same shape was prepared as control. All the disk surfaces were polished using emery papers, #120, #400, and #600. Scanning electron microscopy and a 3D optics profiler were used to evaluate the surface of the materials. In vitro evaluations included colony examination for evaluation of the cell cytotoxicity, DNA quantification for the cell proliferation, Alamar blue assay for metabolic activity, FDA staining for the live cell imaging, and cell cycle analysis, using Chinese hamster fibroblastic V-79 cells and mouse osteoblastic MC3T3-E1 cells. In colony examination and DNA quantification, there was no significant difference between the Ti-Mo-Sn-Zr and the pure titanium. In FDA staining, cultured cells on the Ti-Mo-Sn-Zr alloy showed the same biocompatibility as those on the pure titanium. The present results suggest that the newly developed Ti-Mo-Sn-Zr alloy showed the high biocompatibility comparable to pure titanium and can be used as efficient biomaterial for medical use.


[Guideline on functional abdominal pain in children].
- The guideline entitled 'Functional abdominal pain in children' has been developed by a multidisciplinary working group on behalf of the Dutch Pediatric Association in 2015. - History and physical examination are essential in diagnosing pediatric functional abdominal pain. Additional diagnostic testing is of limited value when alarm symptoms are absent. - Reassurance and education of both the child and parent(s), are the cornerstones in the treatment of pediatric functional abdominal pain. - In case of persisting symptoms, hypnotherapy or cognitive behavioral therapy can be started. There is no evidence for any pharmacological treatment.


An Evaluation of Glucagon Injection Anxiety and Its Association with the Fear of Hypoglycemia among the Parents of Children with Type 1 Diabetes
Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration. Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA). Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child's age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration. The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents' self-confidence including annual refresher training for home glucagon administration.


T cell migration requires ion and water influx to regulate actin polymerization.
Migration of T cells is essential for their ability to mount immune responses. Chemokine-induced T cell migration requires WNK1, a kinase that regulates ion influx into the cell. However, it is not known why ion entry is necessary for T cell movement. Here we show that signaling from the chemokine receptor CCR7 leads to activation of WNK1 and its downstream pathway at the leading edge of migrating CD4+ T cells, resulting in ion influx and water entry by osmosis. We propose that WNK1-induced water entry is required to swell the membrane at the leading edge, generating space into which actin filaments can polymerize, thereby facilitating forward movement of the cell. Given the broad expression of WNK1 pathway proteins, our study suggests that ion and water influx are likely to be essential for migration in many cell types, including leukocytes and metastatic tumor cells.


Lung involvement in Langerhans' cell histiocytosis: prevalence, clinical features, and outcome.
In Langerhans' cell histiocytosis, the prognostic significance of pulmonary disease is controversial. The clinical and radiological features and lung function tests of Langerhans' cell histiocytosis patients presenting to a single tertiary referral center between 1981 and 1987 were reviewed. Age at diagnosis ranged from 2 weeks to 16 years (median 1.7 years) and the male-female ratio was 2.4:1. No child presented with lung involvement alone. In 18 (40%) of 45 patients with multisystem disease there was clinical and/or radiological evidence of lung pathology. Another 6 children (13%) with normal chest roentgenograms had abnormal lung function tests, suggesting subclinical ("occult") involvement. Those with overt lung disease tended to present at a younger than average age (median 0.6 years). The most common functional disturbance was reduced lung or respiratory compliance with reduced lung volumes. Patients with and without lung involvement showed a similar pattern of involvement of other organs, with skin and bone most commonly affected. Of the 45 children with multisystem disease, 38 (84%) survived 2 to 7 years after diagnosis; there was a similar proportion of deaths in children with and without lung involvement. It is concluded that lung involvement occurs in nearly half of young children with multisystem Langerhans' cell histiocytosis but does not adversely affect outcome.


Restriction fragment analysis of a Candida tropicalis outbreak of sternal wound infections.
An apparent single-source outbreak of Candida tropicalis sternal wound infections in eight patients was investigated by utilizing DNA restriction fragment analysis (RFA) with HindIII and BstNI. All eight outbreak isolates appeared to be identical and were easily differentiated from control isolates by DNA RFA. Compared with an arbitrarily selected reference outbreak isolate, greater than or equal to 95% of the bands in the restriction digests identified by a computerized image analysis system from each of the outbreak isolates were identical versus 13 to 53% of the bands in any of the nine control isolates. Outbreak strains were significantly more likely to match the reference outbreak isolate than were controls (P less than 0.0001). The RFA was greatly facilitated by the use of computerized image analysis and confirmed the epidemiologic link between a scrub nurse and the infected patients.


Uterine bacterial flora in postpartum Danish Holstein dairy cows determined using DNA-based fingerprinting: correlation to uterine condition and calving management.
The overall aim of this study was to describe uterine bacterial flora during the postpartum period in Danish Holstein cows using the Terminal Restriction Fragment Length Polymorphism (T-RFLP) method. This method produces a pattern of nucleic acid fragments from the microorganisms present, reflecting the "fingerprint" of the actual microbial flora. As well as characterizing changes in flora with time from calving and between herds, data were examined for strong relations between uterine bacterial flora, calving management and uterine condition. In total 125 Holstein cows from five herds were included, and for each cow calving management was recorded. Cows were clinically examined on average 8 (range 0-19) and 28 (range 22-38) days after calving, and a uterine sample was taken for bacterial identification using T-RFLP. Milk samples were taken weekly for progesterone analysis. Bacteria were found in all cows at both examinations, and the flora was composed of many species, including species not traditionally reported to be present in the bovine uterus. The bacterial composition differed according to days from calving and herd. In all five herds Fusobacterium necrophorum, Pseudomonas/Acinetobacter and Bacteroides/Sphingobacterium/Prevotellaceae were among the most common at both examinations. In four herds there was a percentage decrease of F. necrophorum from first to second examination, and in all herds there was a percentage increase of Pseudomonas/Acinetobacter from first to second examination. No differences in bacterial flora were found between cows with different uterine scores, which were influenced by herd, calving difficulty and retained placenta.


Subclinical hyperthyroidism and biatrial function and mechanics: a two- and three-dimensional echocardiographic study.
We sought to evaluate left atrial (LA) and right atrial (RA) phasic function and deformation in the subclinical hyperthyroidism (SCH) using two- and three-echocardiographic (2DE and 3DE) methods. We included 45 untreated women with SCH and 45 healthy women who underwent comprehensive 2DE and 3DE examination. Total and passive LA emptying fractions (EF) were decreased, whereas active EF was increased among the SCH participants. RA total EFs were similar between the controls and the SCH subjects; passive EF was reduced; and active EF was amplified in the SCH group. TSH correlated with 2DE LA passive and active EFs, 3DE LA total, passive and active EFs, as well as 2DE LA positive longitudinal strain. Additionally, TSH correlated with 2DE RA passive and active EFs, 3DE LA and RA passive EF, 2DE LA and RA positive longitudinal strain. However, after adjustment for the parameters of left and right ventricular diastolic function and structure, the TSH level remained associated only with LA conduit and booster pump functions, as well as RA pump function. Biatrial phasic function evaluated by 2DE and 3DE is significantly impaired in the SCH subjects. TSH level correlates with LA and RA conduit and pump functions.


Studies on the development of a mating disruption system to control the tomato leafminer, Tuta absoluta Povolny (Lepidoptera: Gelechiidae).
The tomato leafminer (Tuta absoluta Povolny) has rapidly colonised the whole Mediterranean and South-Atlantic coasts of Spain, and it has become a key problem in both outdoor and greenhouse crops. New control methods compatible with biological control are required, and mating disruption appears to be a perfect method in current agriculture, as it is an environmentally friendly and residue-free technique. IPM packages tested have included the use of pheromones to detect populations, but there has not been much previous research on mating disruption of T. absoluta. In this work, pheromone doses varying from 10 to 40 g ha(-1), emitted at a constant rate over 4 months, were tested in greenhouses with different levels of containment in order to evaluate the efficacy of mating disruption on T. absoluta. Trials on containment level revealed that the flight of T. absoluta was satisfactorily disrupted with an initial pheromone dose of 30 g ha(-1), and levels of damage did not significantly differ from those in reference plots with insecticide treatments. Later efficacy trials confirmed previous experiences, and release studies showed that control of damage and flight disruption were taking place when releasing at least 85 mg pheromone per ha per day. Effective control using pheromone application against T. absoluta can be achieved, in greenhouses with high containment levels, for 4 months, with initial doses of 30 g ha(-1). Further research must be conducted in order to evaluate the prospect of outdoor application of mating disruption systems.


Antitumor effect of TW-37, a BH3 mimetic in human oral cancer.
TW-37 is a small molecule B cell lymphoma-2 (Bcl-2) homology 3 mimetic with potential anticancer activities. However, the in vivo anti-cancer effect of TW-37 in human oral cancer has not been properly studied yet. Here, we attempted to confirm antitumor activity of TW37 in human oral cancer. TW-37 significantly inhibited cell proliferation and increased the number of dead cells in MC-3 and HSC-3 human oral cancer cell lines. TW-37 enhanced apoptosis of both cell lines evidenced by annexin V/propidium iodide double staining, sub-G1 population analysis and the detection of cleaved poly (ADP-ribose) polymerase and caspase-3. In addition, TW-37 markedly downregulated the expression of Bcl-2 protein, while not affecting Bcl-xL or myeloid cell leukemia-1. In vivo, TW-37 inhibited tumor growth in a nude mice xenograft model without any significant liver and kidney toxicities. Collectively, these data reveal that TW-37 may be a promising small molecule to inhibit human oral cancer.


Detection of Anomalous Patterns Associated with the Impact of Medications on 30-Day Hospital Readmission Rates in Diabetes Care.
Improving quality of care in diabetes requires a good understanding of variations in diabetes outcomes and related interventions. However, little is known about the impact of diabetes interventions on outcome measures at the subpopulation-level. In this study, we developed methods that combine causal inference techniques with subset scanning techniques to study the heterogeneous effects of treatments on binary health outcomes. We analyzed a diabetes dataset consisting of 70,000 initial inpatient encounters to investigate the anomalous patterns associated with the impact of 4 anti-diabetic medication classes on 30-day readmission in diabetes. We discovered anomalous subpopulations where the likelihood of readmission was up to 1.8 times higher than that of the overall population suggesting subpopulation-level heterogeneity. Identifying such subpopulations may lead to a better understanding of the heterogeneous effects of treatments and improve targeted intervention planning.


Evaluation of the anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and Carthamus tinctorius in rats.
The decoction of combined Panax notoginseng (Burk) F.H. Chen and Carthamus tinctorius L. has a history of use in traditional medicine for the prevention and treatment of cardiovascular diseases such as angina pectoris and myocardial infarction. In this study, we investigated the effects of individual herbal extracts and combined extracts on anti-myocardial ischemia injuries in vivo, and determined the proper dosage of Panax notoginseng (EPN) combined with Carthamus tinctorius (ECT) that could strengthen their cardio-protective effects. Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. SD rats were orally given individual EPN 50, 100mg/kg, ECT 100, 200mg/kg, and different combinations between them. Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 24h. Infarct area was determined with 2,3,5-triphenyltetrazolium chloride (TTC) staining. The biomarkers related to myocardial ischemia injury were determined. Simultaneously, hemodynamic parameters were monitored as left ventricular systolic pressure (LVSP), LV end-diastolic pressure (LVEDP) and maximal rate of increase and decrease of left ventricular pressure (dP/dt(max)). The oxidative stress indicators and inflammatory factors were also evaluated. The results showed EPN or ECT significantly reduced infarct size, improved cardiac function, decreased levels of creatine kinase (CK) and lactate dehydrogenase (LDH) (all P<0.05 vs. control ). EPN or ECT alone also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) activity (all P<0.05 vs. control). However, this cardio-protective effect was further strengthened by their combinations. Among all the combinations, EPN 50mg/kg plus ECT 200mg/kg showed predominant potential to reduce infarct size (22.21±1.72%, P<0.05 vs. each single, respectively), preserve cardiac function (P<0.05 vs. ECT 200mg/kg for LVEDP and -dP/dt(max)) after myocardial ischemia injury in rats. This heart protection was confirmed with the lowered cardiac troponin I (cTnI) (P<0.05 vs. ECT 200mg/kg and EPN 50mg/kg, respectively). Oxidative stress and inflammation are the two key factors in the pathogenesis of myocardial ischemia injury. In the present study, EPN 50mg/kg plus ECT 200mg/kg markedly increased SOD and GSH-Px activity (475.30±23.60U/ml, P<0.05 vs. each single, respectively), while elevated MDA level was significantly depressed. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-1β (IL-1β). These results demonstrated EPN, ECT and their combinations exhibited significant cardio-protective effects. The findings suggest EPN combined with ECT may be therapeutically more useful for ameliorating anti-myocardial ischemia injuries than individual herbal extract, and EPN 50mg/kg plus ECT 200mg/kg is the appropriate combination in the present research. The cardio-protective effect of this combination was achieved partially by decreasing oxidative stress and repressing inflammatory cascade.


Vocational training and beyond--listening to voices from a void.
This paper is written from the viewpoint of a doctor who has recently undergone general practice vocational training, and has first-hand experience of some of the opportunities, difficulties, and uncertainties facing doctors at this stage of their careers. The literature on vocational training and the issues concerning young doctors are explored in the light of concerns that recruitment into general practice is falling, that registrars may feel lost in a 'void' at the end of training, and that the 'new world' of post-training work brings problems for many new general practitioners (GPs). Instead of a traditional partnership, one of the authors (RB) chose a salaried, educationally oriented introduction to inner-city general practice. Some innovative, educational schemes, which are aiming to improve the appeal of general practice, are discussed.


Fermented Dairy Products, Probiotic Supplementation, and Cardiometabolic Diseases: A Systematic Review and Meta-analysis.
Fermented dairy foods (FDFs) and probiotics are promising tools for the prevention and management of cardiometabolic diseases (CMDs), respectively. The relation between the regular consumption of FDFs and CMD risk factors was assessed by prospective cohort studies (PCSs), and the effect of probiotic supplementation added into a dairy matrix on CMD parameters was evaluated by randomized controlled trials (RCTs). Moreover, the effects of probiotic supplementation added into a dairy matrix were compared with those administered in capsule/powder form. Twenty PCSs and 52 RCTs met the inclusion criteria for the systematic review and meta-analysis. In PCSs, fermented milk was associated with a 4% reduction in risk of stroke, ischemic heart disease, and cardiovascular mortality [RR (95% CI); 0.96 (0.94, 0.98)]; yogurt intake was associated with a risk reduction of 27% [RR (95% CI); 0.73 (0.70, 0.76)] for type 2 diabetes (T2D) and 20% [RR (95% CI); 0.80 (0.74, 0.87)] for metabolic syndrome development. In RCTs, probiotic supplementation added into dairy matrices produced a greater reduction in lipid biomarkers than when added into capsules/powder in hypercholesterolemic subjects, and probiotic supplementation by capsules/powder produced a greater reduction in T2D biomarkers than when added into dairy matrices in diabetic subjects. Both treatments (dairy matrix and capsules/powder) resulted in a significant reduction in anthropometric parameters in obese subjects. In summary, fermented milk consumption is associated with reduced cardiovascular risk, while yogurt intake is associated with a reduced risk of T2D and metabolic syndrome development in the general population. Furthermore, probiotic supplementation added into dairy matrices could be considered beneficial for lowering lipid concentrations and reducing anthropometric parameters. Additionally, probiotic capsule/powder supplementation could contribute to T2D management and reduce anthropometric parameters. However, these results should be interpreted with caution due to the heterogeneity of the studies and the different probiotic strains used in the studies. This trial is registered with PROSPERO (CRD42018091791) and the protocol can be accessed at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018091791.


Pessimistic cognitive bias is associated with enhanced reproductive investment in female zebrafish.
Optimistic and pessimistic cognitive biases have been described in many animals and are related to the perceived valence of the environment. We, therefore, hypothesize that such cognitive bias can be adaptive depending on environmental conditions. In reward-rich environments, an optimistic bias would be favoured, whereas in harsh environments, a pessimistic one would thrive. Here, we empirically investigated the potential adaptive value of such bias using zebrafish as a model. We first phenotyped female zebrafish in an optimistic/pessimistic axis using a previously validated judgement bias assay. Optimistic and pessimistic females were then exposed to an unpredictable chronic stress protocol for 17 days, after which fish were euthanized and the sectional area of the different ovarian structures was quantified in both undisturbed and stressed groups. Our results show that zebrafish ovarian development responded to chronic stress, and that judgement bias impacted the relative area of the vitellogenic developmental stage, with pessimists showing higher vitellogenic areas as compared with optimists. These results suggest that pessimism maximizes reproductive investment, through increased vitellogenesis, indicating a relationship between cognitive bias and life-history organismal decisions.


Efficacy of Short-Term Spinal Cord Stimulation in Acute/Subacute Zoster-Related Pain: A Retrospective Study.
Postherpetic neuralgia (PHN) is a refractory condition that impairs the patient's quality of life (QoL), it develops secondary to herpes zoster infection. Therefore, it's important to prevent the transition of acute/subacute zoster-related pain to PHN. Despite of numerous studies, the optimal intervention that reduces PHN incidence is still unknown. We evaluate the efficacy of short-term spinal cord stimulation (stSCS) in patients with refractory acute/subacute zoster-related pain. Retrospective study. Tertiary referral center/teaching hospital. A total of 46 patients who presented with acute/subacute zoster-related pain, and had previously failed conventional therapies, underwent stSCS treatment. Visual analog scale (VAS), Short Form Health Survey 12 items (SF-12), and analgesic consumptions were recorded before stSCS, post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stimulation. The VAS scores at post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stSCS treatment were significantly decreased compared with the baseline score (P < 0.001). Thirty-two patients (69.6%, 32/46) achieved the minimal clinically important difference (MCID), including 18 patients (39.1%, 18/46) who achieved complete pain relief (VASless than orequal to2). During the follow-up period, the efficacy of stSCS didn't decrease and VAS scores were declining. Similarly, SF-12 scores and analgesic consumptions improved after stSCS treatment. The efficacy of stSCS did not differ significantly among patients with different durations of acute/subacute zoster-related pain starting from the onset of rash. No serious adverse effects were observed in the entire follow-up period. This study was not a randomized prospective controlled study. We did not compare the outcomes with patients presenting with mild or moderate pain, and did not compare the efficacy of stSCS treatment with conventional therapies. stSCS is a safe, effective, and less invasive analgesic method for patients with refractory acute/subacute zoster-related pain. Herpes zoster, zoster-related pain, postherpetic neuralgia, spinal cord stimulation, VAS.


The Impact of a City-Wide Indoor Smoking Ban on Smoking and Drinking Behaviors Across Emerging Adulthood.
Almost one-third of college students report recent cigarette use, primarily as "social smoking," and often in conjunction with alcohol use. While city-wide indoor smoking bans effectively reduce the number of social opportunities to smoke (eg, bars and music clubs), little is known about how these bans may impact the smoking behaviors of college students. Furthermore, nothing is known about how indoor smoking bans may impact students' drinking behaviors. The current study aims to determine the impact of a city-wide comprehensive indoor smoking ban on smoking and alcohol behaviors among a longitudinal sample of emerging adults. Data are from a 6-year longitudinal study (10 waves of data collection) that began the summer before college enrollment. Participants (N = 2244; 60% female) reported on their past 3-month smoking and drinking behaviors using Internet-based surveys at each wave. Piecewise linear growth modeling was used to determine how a city-wide comprehensive indoor smoking ban (implemented in the Fall of 2005 between Waves 4 and 5) impacted smoking frequency, cigarette quantity, drinking frequency, and number of binge drinking episodes. Smoking and alcohol use increased from the summer before college through the semester before implementation of the city-wide smoking ban. While smoking frequency (P < .001) and cigarette quantity (P < .05) declined after the ban, drinking frequency increased (P < .001) and the number of binge drinking episodes remained stable. Current findings suggest that comprehensive indoor smoking bans can influence the smoking behaviors of emerging adults, whereas trajectories of drinking are relatively unchanged.


A one-dimensional mixed porohyperelastic transport swelling finite element model with growth.
A one-dimensional, large-strain, mixed porohyperelastic transport and swelling (MPHETS) finite element model was developed in MATLAB and incorporated with a well-known growth model for soft tissues to allow the model to grow (increase in length) or shrink (decrease in length) at constant material density. By using the finite element model to determine the deformation and stress state, it is possible to implement different growth laws in the program in the future to simulate how soft tissues grow and behave when exposed to various stimuli (e.g. mechanical, chemical, or electrical). The essential assumptions needed to use the MPHETS model with growth are clearly identified and explained in this paper. The primary assumption in this work, however, is that the stress upon which growth acts is the stress in the solid skeleton, i.e. the effective stress, S(eff). It is shown that significantly different amounts of growth are experienced for the same loading conditions when using a porohyperelastic model as compared to a purely solid model. In one particular example, approximately 51% less total growth occurred in the MPHETS model than in the solid model even though both problems were subjected to the same external loading. This work represents a first step in developing more sophisticated models capable of capturing the complex mechanical and biochemical environment in growing and remodeling tissues.


Microinjection of morphine into the nucleus accumbens impairs contextual learning in rats.
A unilateral microinjection of morphine into the amygdala impaired fear conditioning to both a conditioned stimulus (CS) paired with shock and the context where shock occurred, whereas a microinjection of morphine into the nucleus accumbens (NA) spared fear conditioning to the CS but impaired, in a dose-dependent and receptor-specific manner, fear conditioning to the context. Morphine in the NA also spared extinction and latent inhibition of a CS but abolished the context specificity of these effects and eliminated the increase in discriminability that results from preexposure to a to-be-shocked context. The results identify a role for the NA in the processes by which rats learn about a context and are discussed in terms of an opioid disruption of either within-context associations or of attentional processes that contribute to such associations.


Bond-valence constraints on liquid water structure.
The recent controversy about the structure of liquid water pits a new model involving water molecules in relatively stable "rings-and-chains" structures against the standard model that posits water molecules in distorted tetrahedral coordination. Molecular dynamics (MD) simulations, both classical and ab initio, almost uniformly support the standard model, but because none of them can yet reproduce all of the anomalous properties of water, they leave room for doubt. We argue that it is possible to evaluate these simulations by testing them against their adherence to the bond-valence model, a well-known and quantitatively accurate empirical summary of the behavior of atoms in the bonded networks of inorganic solids. Here we use the results of ab initio MD simulations of ice, water, and several solvated aqueous species to show that the valence sum rule (the first axiom of the bond-valence model) is followed in both solid and liquid bond networks. We then test MD simulations of water, employing several popular potential models against this criterion and the experimental O-O RDF. It appears that most of those tested cannot satisfy both criteria well, except TIP4P, TIP4P/2005, and TIP5P. If the valence sum rule really can be applied to simulated liquid structures, then it follows that the bonding behaviors of atoms in liquids are in some ways identical to those in solids. We support this interpretation by showing that the simulations produce O-H...O geometries that are completely consistent with the range of geometries available in solids, and the distributions of instantaneous valence sums reaching the atoms in both the ice and liquid water simulations are essentially identical. Furthermore, we show that none of the extant asymmetric water potentials that produce "rings-and-chains" structures can satisfy our geometric criteria. Taken together, this is powerful evidence in favor of the standard distorted tetrahedral model of liquid water structure.