Physician practices in evaluation and treatment of patients with generalized joint hypermobility and bleeding.
The association between bleeding and joint hypermobility may not be as diagnostically obvious in patients with milder connective tissue disorders. We surveyed members of the Hemostasis and Thrombosis Research Society regarding their knowledge, evaluation, and management practices in patients with generalized hypermobility spectrum disorder/hypermobile Ehlers-Danlos syndrome (hEDS) and bleeding symptoms. The objectives of this study were to (1) evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS and (2) determine future education and research priorities regarding bleeding symptoms within this population. Evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS. Determine future education and research priorities regarding bleeding symptoms within this population. A web-based survey was sent to Hemostasis and Thrombosis Research Society physician members. Physician demographics, preferred evaluation for hEDS, management of bleeding episodes, and referral patterns were collected and descriptive statistics were performed. Only two-thirds of respondents reported evaluating for hypermobility, despite all respondents being aware of the association with bleeding. There were significant variations in referral patterns for genetic counseling, diagnostic evaluation, and management of nonhematologic symptoms. There were also significant variations in reported medical homes for this patient population. Research prioritization included understanding the evolution of bleeding symptoms with age in this population as well as the development of functional tests to identify the molecular mechanism of bleeding and the development of novel hemostatic agents for this population. Results from 33 respondents show differing physician practices regarding the evaluation and management of bleeding in hypermobile patients. Many physicians suggested further research priorities to include studying the natural history of the disease and development of functional diagnostic testing as well as targeted therapeutic options in this patient population.


Telomerase activity in the differential diagnosis of papillary carcinoma of the thyroid.
Although fine-needle aspiration (FNA) is 90% sensitive in the detection of papillary carcinoma (PC) of the thyroid, its specificity has been reported as low as 52%. Consequently, patients who have an FNA suspicious for PC may undergo operation for a benign process. The ribonucleoprotein telomerase has been noted to be activated in a wide variety of carcinomas. We examined 30 PCs for telomerase activity to determine whether this would be a useful adjunct to FNA in the diagnosis of lesions suspicious for PC. Standard telomere repeat amplification protocol assays were performed on fresh frozen tissue samples from 30 PCs, 3 benign nodules, and 10 normal thyroids. Telomerase activity was documented in 20 of 30 (67%) of the PCs, 0 of 3 benign nodules, and 0 of 10 normal thyroids. In all, 11 of the 20 PCs had FNA cytology that was nondiagnostic of PC, and 2 of the benign nodules had FNA that was suspicious for PC. The telomerase assay appears useful in the distinction of benign from malignant thyroid lesions that have FNA suspicious for but not diagnostic of PC. On the basis of these findings, a prospective trial examining telomerase activity in FNAs suspicious for thyroid cancer has been initiated.


A novel heme a insertion factor gene cotranscribes with the Thermus thermophilus cytochrome ba3 oxidase locus.
Studying the biogenesis of the Thermus thermophilus cytochrome ba(3) oxidase, we analyze heme a cofactor insertion into this membrane protein complex. Only three proteins linked to oxidase maturation have been described for this extreme thermophile, and in particular, no evidence for a canonical Surf1 homologue, required for heme a insertion, is available from genome sequence data. Here, we characterize the product of an open reading frame, cbaX, in the operon encoding subunits of the ba(3)-type cytochrome c oxidase. CbaX shares no sequence identity with any known oxidase biogenesis factor, and CbaX homologues are found only in the Thermaceae group. In a series of cbaX deletion and complementation experiments, we demonstrate that the resulting ba(3) oxidase complexes, affinity purified via an internally inserted His tag located in subunit I, are severely affected in their enzymatic activities and heme compositions in both the low- and high-spin sites. Thus, CbaX displays typical features of a generic Surf1 factor essential for binding and positioning the heme a moiety for correct assembly into the protein scaffold of oxidase subunit I.


Surgical treatments in inferior oblique muscle overaction.
To compare the outcomes of surgical procedures in the treatment of inferior oblique muscle overaction (IOOA) as a common disorder of ocular motility. This retrospective study was performed on patients with primary and secondary IOOA who underwent three surgical treatment procedures including disinsertion, myectomy and anterior transposition, between 2001 and 2011. Type of strabismus, ocular alignment, presence of pre-and post-operative dissociated vertical deviation (DVD), pre- and post-operative degree of IOOA were obtained using specified checklist. A total of 122 eyes of 74 patients with mean age of 13 ± 11.7 (range, 1-51) years were included in this study. Disinsertion was performed on 12 eyes (9.8%), myectomy in 91 eyes (74.6%) and anterior transposition in 19 (15.6%). Preoperative V-pattern and DVD existed in 67 and 17 eyes; after surgery they remained in only 10 and 8 eyes, respectively. The success rate (IOOA <+1), in disinsertion, myectomy and anterior transposition groups were 91.7%, 97.8%, and 89.5%, respectively and these measures did not change after 6 months. Overall, 53.3% (n = 65) and 38.5% (n = 47) of eyes had preoperative esotropia and exotropia. Preoperative hypertropia and hypotropia were observed in 16.4% (n = 20) and 3.3% (n = 4) of eyes, respectively. After surgery there were no cases of additional strabismus. However, residual hypertropia was seen in 9 eyes, while preoperative hypotropia increased in one patient who underwent anterior transposition surgery. Esotropia and exotropia were not observed in any surgical treatment groups postoperatively. We conclude that all these three procedures are effective for treatment of primary or secondary IOOA with minimum side-effects.


Autosomal dominant pure spastic paraplegia: a clinical, paraclinical, and genetic study.
At least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP) have been described. In this study the clinical, genetic, neurophysiological, and MRI characteristics of ADPSP were investigated. Sixty three at risk members from five families were clinically evaluated. A diagnostic index was constructed for the study. Microsatellite genotypes were determined for chromosomes 2p, 14q, and 15q markers and multipoint linkage analyses were performed. Central motor conduction time studies (CMCT), somatosensory evoked potential (SSEP) measurement, and MRI of the brain and the total spinal cord were carried out in 16 patients from four families. The clinical core features of ADPSP were homogeneously expressed in all patients but some features were only found in some families and not in all the patients within the family. In two families non-progressive "congenital" ADPSP was seen in some affected members whereas adult onset progressive ADPSP was present in other affected family members. As a late symptom not previously described low backache was reported by 47%. Age at onset varied widely and there was a tendency for it to decline in successive generations in the families, suggesting anticipation. Genetic linkage analysis confined the ADPSP locus to chromosome 2p21-p24 in the five families. The lod scores obtained by multipoint linkage analysis were positive with a combined maximum lod score of Z=8.60. The neurophysiological studies only showed minor and insignificant prolongation of the central motor conduction time and further that peripheral conduction and integrity of the dorsal columns were mostly normal. Brain and the total spinal cord MRI did not disclose any significant abnormalities compared with controls. ADPSP linked to chromosome 2p21-p24 is a phenotypic heterogeneous disorder characterised by both interfamilial and intrafamilial variation. In some families the disease may be "pure" but the existence of "pure plus" families is suggested in others. The neurophysiological and neuroimaging investigations did not show any major abnormalities.


[Spectral changes of C-phycocyanin with different molar ratios of SPDP].
Pure C-phycocyanin was prepared from Spirulina platensis using one-step anion-exchange chromatography. The C-PC obtained was with an absorption maximum at 620 nm and a fluorescence emission maximum at 640 nm when excited by 580 nm. SPDP is an excellent heterobifunctional crosslinker for thiolating amines. Different molar ratios of SPDP have remarkable influence on the absorption and fluorescence spectra of C-phycocyanin. The absorption maximum and fluorescence emission maximum both decreased and blue-shifted from 640 nm to 630 nm as the molar ratios of SPDP increased. It was found that the molar ratios of SPDP to C-phycocyanin was not more than 100 was appropriate to being conjugated with other biomolecules from the absorption and fluorescence spectra of C-phycocyanin.


Assessment of novel biomarkers: sTREM-1, pentraxin-3 and pro-adrenomedullin in the early diagnosis of neonatal early onset sepsis.
Early onset bacterial sepsis in neonates (EOS) is recognized as an important health condition. Early diagnosis is crucial. However, blood culture results are released in 48-72 hours. Many biomarkers have been investigated but none have been accepted as the gold standard. This study aimed to investigate the diagnostic value of the molecules: soluble form of triggering receptor expressed on myeloid cells-1 (sTREM-1), pentraxin-3 (PTX-3) and pro adrenomedullin (pro-ADM) in EOS and compare with currently used biomarkers. In this multicenter prospective study, patients were enrolled from different NICUs around the Turkey. Patient data were collected via web-based registry system from attending centers. Neonates, hospitalized with a suspicion of EOS were enrolled. Blood culture and routine blood tests were collected and a serum sample was obtained and kept in - 80°C for studying the molecules. According to laboratory results, patients were divided into three groups as; proven sepsis, clinical sepsis and control group. Groups were compared in terms of demographic, clinical and laboratory findings. The primary outcome of the study was to assess any difference between groups in terms of the diagnostic value of the markers aforementioned. A total of 130 patients were enrolled; proven sepsis (n = 36), clinical sepsis (n = 53) and control (n = 41) groups. Groups were similar in terms of demographic findings; mean WBC (P = 0.445), procalcitonin (PCT) (P = 0.083) and IL-6 (P = 0.814) levels. Mean C-reactive protein (CRP) level was significantly higher in clinical sepsis and proven sepsis groups compared to control group (P < 0.001). Mean PTX-3 (P = 0.547), pro-ADM (P = 0.766) and sTREM-1 (P = 0.838) levels were similar between groups. These promising molecules failed to help in early diagnosis of EOS. Their relation to correlation with disease progression may make more sense as they seem to be expressed in higher amounts with the progression of the disease in previous studies. CRP was the most frequently used biomarker for detecting the sepsis in our study population.


Effects of some natural carotenoids on TRPA1- and TRPV1-induced neurogenic inflammatory processes in vivo in the mouse skin.
Mechanisms of the potent anti-inflammatory actions of carotenoids are unknown. Since carotenoids are incorporated into membranes, they might modulate transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1) activation predominantly on peptidergic sensory nerves. We therefore investigated the effects of three carotenoids (β-carotene, lutein and lycopene) on cutaneous neurogenic inflammation. Acute neurogenic edema and inflammatory cell recruitment were induced by smearing the TRPA1 agonist mustard oil (5%) or the TRPV1 activator capsaicin (2.5%) on the mouse ear. Ear thickness was then determined by micrometry, microcirculation by laser Doppler imaging and neutrophil accumulation by histopathology and spectrophotometric determination of myeloperoxidase activity. The effects of lutein on the stimulatory action of the TRPA1 agonist mustard oil were also tested on the guinea-pig small intestine, in isolated organ experiments. Mustard oil evoked 50-55% ear edema and granulocyte influx, as shown by histology and myeloperoxidase activity. Swelling was significantly reduced between 2 and 4 h after administration of lutein or β-carotene (100 mg/kg subcutane three times during 24 h). Lutein also decreased neutrophil accumulation induced by TRPA1 activation, but did not affect mustard oil-evoked intestinal contraction. Lycopene had no effect on any of these parameters. None of the three carotenoids altered capsaicin-evoked inflammation. It is proposed that the dihydroxycarotenoid lutein selectively inhibits TRPA1 activation and consequent neurogenic inflammation, possibly by modulating lipid rafts.


Influence of dose and route of antigen injection on the immunological induction of T cells.
Delayed-type hypersensitivity (DTH) develops in the absence of an adjuvant when mice are injected intravenously or subcutaneously with an appropriate dose of sheep red blood cells (SRBC). The optimal intravenous dose of 10(5) SRBC (in CD-1 mice) produces maximum DTH which decays exponentially from its peak on day 4. Increasing the dose of SRBC reduces and eventually abolishes all evidence of DTH. DTH fails to reappear in respose to secondary stimulation except in splenectomized mice in whom the development of DTH is not suppressed, even by massive doses of SRBC. Hence the suppression cannot be due to antigen as such. The optimal dose of SRBC for sensitization by footpad inoculation is 100-fold higher (10(7) SRBC in CD-1 mice), but even 10(9) SRBC do not block the induction of DTH by this route of immunization. A blocking dose of SRBC, given intravenously 1 day before footpad inoculation, completely suppresses cell proliferation in the draining lymph node, prevents PFC production there, and blocks the induction of DTH by a sensitizing dose of SRBC. If given 1 day after footpad sensitization, intravenous antigen has little effect on the cellular response in the regional node but DTH is still completely suppressed. Blocking of induction and expression may depend, therefore, on different mechanisms.


The development of prescribing incentive schemes in primary care: a longitudinal survey.
Primary Care Groups and Trusts in England (Primary Care Organisations, or PCOs) are required to operate a prescribing incentive scheme. Little is known about their development since their inception in 1999. We surveyed incentive schemes in London and the South-East NHS Regions in the two consecutive years since 1999. Most of the changes to the incentives and prescribing indicators favoured improvements in prescribing quality, rather than cost control. Quality improvements may be hampered in those PCOs offering financial rewards to underspent general practices that fail to achieve any prescribing quality targets.


Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy.
Survivin is a novel attractive target for cancer therapy; however, it is considered undruggable because it lacks enzymatic activities. Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110. Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cells A549 with an IC50 value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells. Further biological studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy. Furthermore, the promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by the overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (KD = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.


HER2 as a target in invasive urothelial carcinoma.
We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥ 2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.


Isolation and characterization of pso mutants sensitive to photo-addition of psoralen derivatives in Saccharomyces cerevisiae.
We have isolated mutants sensitive to photo-addition of bi-functional and mono-functional derivatives of psoralen in Saccharomyces cerevisiae. Three of these pso mutants were analyzed in detail. They segregate in meiosis like Mendelian genes and complement each other, as well as existing radiation-sensitive (rad and rev) mutants. The study of heterozygous diploid strains (PSO+/pso) indicates that the three pso genes are recessive. The mutant pso1--1 demonstrates a cross-sensitivity to UV and gamma-rays, whereas mutants pso2--1 and pso3--1 are specifically sensitive to photo-addition of psoralen derivatives. The comparison of exponentially growing cells to stationary-phase cells demonstrates that for the three mutants the defect in repair capacity of DNA cross-links and monoadducts concerns G1 and early S-phase cells. The pso2--1 mutant is, however, also defective in G2 repair and loses diploid resistance when it is in the homozygous state.--The block in repair capacity in these novel mutants is discussed in relation to the three other repair pathways known to be involved in the repair of furocoumarins photo-induced lesions in yeast DNA.


Effectiveness of Light Therapy in Cognitively Impaired Persons: A Metaanalysis of Randomized Controlled Trials.
To explore the effects of light therapy on behavioral disturbances (BDs), sleep quality, and depression. Meta-analysis of randomized controlled trials. PubMed, Cochrane Library, Medline, EMBASE, Web of Science, and clinicaltrials.gov of selected randomized controlled trials and previous systematic reviews were searched. Cognitively impaired persons. Information was extracted on study characteristics, quality assessment, and outcomes. Outcome measures included BDs, sleep quality, and depression. Nine randomized controlled trials were examined. The results showed that light therapy has a moderate effect on BD (g = -0.61) and depression (g = -0.58) and a small effect on total sleep time at night (g = 0.25). Subgroup analysis indicated that a light intensity of 2,500 lux or greater has a greater effect on depression than an intensity of less than 2,500 lux (P = .03), and the low risk of bias in blinding was superior to the RCTs deemed to be of high or unclear risk of bias in blinding in terms of BD (P = .02). Light therapy can relieve BD, improve sleep quality, and alleviate symptoms of depression for cognitively impaired persons.


Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation.
Vitamin D, an important modulator of the immune system, has been shown to protect mucosal barrier homeostasis. This study investigates the effects of vitamin D deficiency on infection-induced changes in intestinal epithelial barrier function in vitro and on Citrobacter rodentium-induced colitis in mice. Polarized epithelial Caco2-bbe cells were grown in medium with or without vitamin D and challenged with enterohemorrhagic Escherichia coli O157:H7. Barrier function and tight junction protein expression were assessed. Weaned C57BL/6 mice were fed either a vitamin D-sufficient or vitamin D-deficient diet and then infected with C. rodentium. Disease severity was assessed by histological analysis, intestinal permeability assay, measurement of inflammatory cytokine levels, and microbiome analysis. 1,25(OH)2D3 altered E. coli O157:H7-induced reductions in transepithelial electrical resistance (P < .01), decreased permeability (P < .05), and preserved barrier integrity. Vitamin D-deficient mice challenged with C. rodentium demonstrated increased colonic hyperplasia and epithelial barrier dysfunction (P < .0001 and P < .05, respectively). Vitamin D deficiency resulted in an altered composition of the fecal microbiome both in the absence and presence of C. rodentium infection. This study demonstrates that vitamin D is an important mediator of intestinal epithelial defenses against infectious agents. Vitamin D deficiency predisposes to more-severe intestinal injury in an infectious model of colitis.


Requirement of a properly acylated beta(1-6)-D-glucosamine disaccharide bisphosphate structure for efficient manifestation of full endotoxic and associated bioactivities of lipid A.
Several synthetic acylated glucosamine monophosphates, with structures corresponding to the nonreducing or reducing moiety of the lipid A of the Escherichia coli or Salmonella minnesota type, and a synthetic compound corresponding to a biosynthetic disaccharide lipid A precursor (designated Ia or IVA) were examined for their endotoxic and related bioactivities in comparison with those of the synthetic and bacterial parent molecules, i.e., acylated beta(1-6)-D-glucosamine disaccharide bisphosphates. Some of the test monosaccharide compounds were definitely active in most of the in vitro assays. Their activities, except for complement activation, however, were weaker than those of the reference compounds, synthetic and bacterial acylated disaccharide bisphosphates. The differences between the test monosaccharide and disaccharide compounds were much more apparent in in vivo assays, in which the test acylated glucosamine monophosphates were scarcely active, though some test compounds exhibited weak lethal toxicity in galactosamine-loaded mice and were weakly active in pyrogenicity, immunoadjuvant activity, and possible tumor necrosis factor and alpha and beta interferon-inducing ability in Mycobacterium bovis BCG- and Propionibacterium acnes-primed mice, respectively. Mixture at an equimolar ratio of acyl glucosamine monophosphates, each of which has the structure of the reducing or nonreducing moiety of the reference disaccharide compound, did not restore the endotoxic or associated bioactivities of the corresponding parent molecules. No essential differences in bioactivity were noted between synthetic and bacterial monosaccharide compounds, i.e., lipid X, whose structure corresponds to the reducing moiety of E. coli-type lipid A.


Quercetin Prevents Lipopolysaccharide-Induced Experimental Preterm Labor in Mice and Increases Offspring Survival Rate.
Premature labor is still a worldwide problem, causing serious social economic burden and family burden. Currently, there is no effective way to prevent preterm labor. Since inflammation increases the risk of preterm birth and quercetin is reported to have anti-inflammation, immune-enhancement, and antioxidative effects, this study aims to explore whether quercetin exerts inhibitory effect on preterm labor in mice and increases offspring survival. Lipopolysaccharide (LPS) is one of the commonly used drugs in the inflammatory animal model of preterm birth. On day 15 of pregnancy, mice received a dose of vehicle phosphate-buffered saline (PBS) or a dose of quercetin (low concentration, 30 mg/kg; medium concentration, 90 mg/kg; high concentrations, 150 mg/kg) via oral gavage. After 2 h, mice received a dose of LPS (50 μg/kg) or vehicle intraperitoneally (i.p.). In the absence of quercetin, a 100% incidence of preterm labor was observed in LPS-treated mice, and the fetuses were all died. Medium concentration of quercetin significantly prevented 63.5% of LPS-induced inflammatory preterm labor, and the survival rate of pups on day 22 was 83.76%. Specifically, quercetin significantly inhibited LPS-induced upregulation of NF-kappa-B/P65(RELA), AP-1/C-JUN(JUN), cyclooxygenase-2(PTGS2), and interleukin 6(IL6) in mice myometrium on mRNA level and inhibited the upregulation of P65 and C-JUN on protein level. Based on these observations, we concluded that quercetin exerts inhibitory effect on LPS-induced experimental mice preterm labor and increases offspring survival through a mechanism involving NF-κB/AP-1 pathway.


Immunosuppression and Chagas disease: a management challenge.
Immunosuppression, which has become an increasingly relevant clinical condition in the last 50 years, modifies the natural history of Trypanosoma cruzi infection in most patients with Chagas disease. The main goal in this setting is to prevent the consequences of reactivation of T. cruzi infection by close monitoring. We analyze the relationship between Chagas disease and three immunosuppressant conditions, including a description of clinical cases seen at our center, a brief review of the literature, and recommendations for the management of these patients based on our experience and on the data in the literature. T. cruzi infection is considered an opportunistic parasitic infection indicative of AIDS, and clinical manifestations of reactivation are more severe than in acute Chagas disease. Parasitemia is the most important defining feature of reactivation. Treatment with benznidazole and/or nifurtimox is strongly recommended in such cases. It seems reasonable to administer trypanocidal treatment only to asymptomatic immunosuppressed patients with detectable parasitemia, and/or patients with clinically defined reactivation. Specific treatment for Chagas disease does not appear to be related to a higher incidence of neoplasms, and a direct role of T. cruzi in the etiology of neoplastic disease has not been confirmed. Systemic immunosuppressive diseases or immunosuppressants can modify the natural course of T. cruzi infection. Immunosuppressive doses of corticosteroids have not been associated with higher rates of reactivation of Chagas disease. Despite a lack of evidence-based data, treatment with benznidazole or nifurtimox should be initiated before immunosuppression where possible to reduce the risk of reactivation. Timely antiparasitic treatment with benznidazole and nifurtimox (or with posaconazole in cases of therapeutic failure) has proven to be highly effective in preventing Chagas disease reactivation, even if such treatment has not been formally incorporated into management protocols for immunosuppressed patients. International consensus guidelines based on expert opinion would greatly contribute to standardizing the management of immunosuppressed patients with Chagas disease.


Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.
Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440,000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the infrastructure necessary to manage MDR tuberculosis on a national scale.


Parental weight changes as key predictors of child weight changes.
Parents are the key agents of behavioural changes in their children. This fact is as an important aspect of obesity treatment and prevention. The present study aims to evaluate the influence of parents who have gained or lost weight on their children's weights and to examine parental and child patterns of weight changes from a baseline over a 14-year duration. We performed a secondary analysis on the Indonesia Family Life Survey (IFLS), an ongoing national prospective longitudinal cohort study in Indonesia. Height and weight measurements, information regarding parental education, maternal employment, household income, and residence were collected from children under five years old (n = 3,147) and their parents in 1993. Data were taken from the same individuals at different points in time, in 1997, 2000, and 2007. During each transition, the children of parents who gained weight had a significantly weights than did children of parents who lost weight. A mother's positive weight change increased the chance of her pre-schooler's or school-aged child's positive weight change. However we found no such association between a father's positive weight change and his child's positive weight change. Parental weight change is an independent predictor of child weight change. Positive weight change in the mother had a more dominant influence than did the father's positive weight change. Future family-based obesity prevention and treatment programs should consider how best to include and engage mothers as a catalyst for the reduction of obesity-related risk factors in the long term.


Development of Allograft Cancer after Lung Transplantation: A Case Report.
In contrast to skin cancer and lymphoproliferative disorders, de-novo lung allograft cancer is seldom reported after lung transplantation. A 19-year-old patient with severe pulmonary hypertension listed urgently for lung transplantation underwent successful bilateral lung transplant procedure receiving lungs from a 55-year-old donor with a smoking history of 30 pack years. After 3.5 years of lung transplantation, a locally advanced squamous cell carcinoma in the left lung allograft was diagnosed. Extended (intra-pericardial) left pneumonectomy was successfully performed, but the patient died a few weeks later due to acute respiratory distress syndrome. Usage of extended criteria donors seems a successful strategy to overcome shortage of donor lungs by the increasing number of lung transplant candidates. However, this approach might increase the risk of novel development of lung allograft cancer, a potential fatal complication that must be considered during follow-up of lung transplant recipients.


A two-stage classification approach identifies seven susceptibility genes for a simulated complex disease.
The simulated data set of the Genetic Analysis Workshop 15 provided affection status, four quantitative traits, and a covariate. After studying the relationship between these variables, linkage analysis was undertaken. Analyses were performed in the first replicate only and without any prior knowledge of the underlying model. In addition to the main effect of the DR locus on chromosome 6, significant linkage was also identified on chromosomes 8, 9, 11, and 18. Notably, the power to detect linkage increased after transforming the skewed and kurtotic IgM and anti-CCP distributions. Moreover, genes on chromosome 11 could not be discerned from noise without the transformation, thus highlighting the need in real life situations for careful examination of the phenotypic data prior to genetic analysis. Significant association with one single-nucleotide polymorphism was identified for the regions on chromosome 11 and 18. Haplotype analyses were attempted for the other regions, but only the underlying variation of the DR locus could be identified. Two methods were then applied to predict classification using the factors identified so far. These methods - logistic regression and multifactor dimensionality reduction (MDR) - performed comparably for this data set. Those affected individuals that were misclassified as unaffected were then used in a genome-wide association analysis to identify additional susceptibility loci. Two additional loci were identified in this fashion, illustrating the usefulness of this two-stage classification approach.


[Clinical Research without Direct Profit in Children and the Best Interest Standard].
Clinical research has an ambivalent nature for the benefits it promises and the risks we inevitably incur. When the subjects involved are minors, ethical issues become more complicated. The ethical importance of the matter is revealed especially when assessing clinical trials in which children are exposed to high risk (it can involve even the subject's live), because those children have no legal skill to decide about the question, and when the big institutions (pharmaceutical companies, universities or public institutions) give preference to research 'progress', over the welfare of the minors. In this paper we analyze on which criteria research involving children is uphold, as well as the standards that should be applied in this activity, and we will detain particularly in the valuation of the use of placebo, especially when the children involved in a trial do not receive a direct profit from it.


Standardizing diagnostic markers to evaluate and compare their performance.
Markers that purport to distinguish subjects with a condition from those without a condition must be evaluated rigorously for their classification accuracy. A single approach for statistical evaluation and comparison of markers is not yet established. We suggest a standardization that uses the marker distribution in unaffected subjects as a reference. For an affected subject with marker value Y, the standardized placement value is the proportion of unaffected subjects with marker values that exceed Y. We applied the standardization to 2 illustrative datasets. As a marker for pancreatic cancer, the CA-19-9 marker had smaller placement values than the CA-125 marker, indicating that CA-19-9 was the better marker. For detecting hearing impairment, the placement values for the test output (the marker) were smaller when the input sound stimulus was of lower intensity, which indicates that the test better distinguishes hearing-impaired from unimpaired ears when a lower intensity sound stimulus is used. Explicit connections are drawn between the distribution of standardized marker values and the receiver operating characteristic curve, one established statistical technique for evaluating classifiers. The standardization is an intuitive procedure for evaluating markers. It facilitates direct and meaningful comparisons between markers. It also provides a new view of receiver operating characteristic analysis that may render it more accessible to those as yet unfamiliar with it. The general approach provides a statistical tool to address important questions that are typically not addressed in current marker research, such as quantifying and controlling for covariate effects.


A modified Hopfield auto-associative memory with improved capacity.
This paper describes a new procedure to implement a recurrent neural network (RNN), based on a new approach to the well-known Hopfield autoassociative memory. In our approach a RNN is seen as a complete graph G and the learning mechanism is also based on Hebb's law, but with a very significant difference: the weights, which control the dynamics of the net, are obtained by coloring the graph G. Once the training is complete, the synaptic matrix of the net will be the weight matrix of the graph. Any one of these matrices will fulfill some spatial properties, for this reason they will be referred to as tetrahedral matrices. The geometrical properties of these tetrahedral matrices may be used for classifying the n-dimensional state-vector space in n classes. In the recall stage, a parameter vector is introduced, which is related with the capacity of the network. It may be shown that the bigger the value of the ith component of the parameter vector is, the lower the capacity of the [i] class of the state-vector space becomes. Once the capacity has been controlled, a new set of parameters that uses the statistical deviation of the prototypes to compare them with those that appear as fixed points is introduced, eliminating thus a great number of parasitic fixed points.


Agricultural practices to improve nitrogen use efficiency through the use of arbuscular mycorrhizae: Basic and agronomic aspects.
Nitrogen cycling in agroecosystems is heavily dependent upon arbuscular mycorrhizal fungi (AMF) present in the soil microbiome. These fungi develop obligate symbioses with various host plant species, thus increasing their ability to acquire nutrients. However, AMF are particularly sensitive to physical, chemical and biological disturbances caused by human actions that limit their establishment. For a more sustainable agriculture, it will be necessary to further investigate which agricultural practices could be favorable to maximize the benefits of AMF to improve crop nitrogen use efficiency (NUE), thus reducing nitrogen (N) fertilizer usage. Direct seeding, mulch-based cropping systems prevent soil mycelium disruption and increase AMF propagule abundance. Such cropping systems lead to more efficient root colonization by AMF and thus a better establishment of the plant/fungal symbiosis. In addition, the use of continuous cover cropping systems can also enhance the formation of more efficient interconnected hyphal networks between mycorrhizae colonized plants. Taking into account both fundamental and agronomic aspects of mineral nutrition by plant/AMF symbioses, we have critically described, how improving fungal colonization through the reduction of soil perturbation and maintenance of an ecological balance could be helpful for increasing crop NUE.


Genomic insight into variants associated with flowering-time and early-maturity in pigeonpea mutant TAT-10 and its wild type parent T21.
Pigeonpea [Cajanus cajan (L.) Millspaugh] is an important grain legume crop with a broad range of 90 to 300 days for maturity. To identify the genomic variations associated with the early maturity, we conducted whole-genome resequencing of an early-maturing pigeonpea mutant TAT-10 and its wild type parent T21. A total of 135.67 and 146.34 million sequencing reads were generated for T21 and TAT-10, respectively. From this resequencing data, 1,397,178 and 1,419,904 SNPs, 276,741 and 292,347 InDels, and 87,583 and 92,903 SVs were identified in T21 and TAT-10, respectively. We identified 203 genes in the pigeonpea genome that are homologs of flowering-related genes in Arabidopsis and found 791 genomic variations unique to TAT-10 linked to 94 flowering-related genes. We identified three candidate genes for early maturity in TAT-10; Suppressor of FRI 4 (SUF4), Early Flowering In Short Days (EFS), and Probable Lysine-Specific Demethylase ELF6. The variations in ELF6 were predicted to be possibly damaging and the expression profiles of EFS and ELF6 also supported their probable role during early flowering in TAT-10. The present study has generated information on genomic variations associated with candidate genes for early maturity, which can be further studied and exploited for developing the early-maturing pigeonpea cultivars.


Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation.
We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.


[Clinical factors influencing the complications and survival of liver transplantation in Hungary].
Clinical factors in association with the complications and the outcome of liver transplantation. The Hungarian experience. Demography, morbidity, perioperative characteristics and mortality. The authors summarize the demographic, morbidity and mortality characteristics of the Hungarian Liver Transplant Program. They evaluate the changes and development, that has taken place with regard to indications, recipient population and characteristics, operation technique, and peroperative patient management. In order to present the development, data are compared between two time periods (before and after 1999). Categorical variables are evaluated by chi-square test, continuous ones are with Levene Test (for homogeneity of means), Student T test and Mann-Whitney U-test. Cumulative survivals are computed with Kaplan-Meyer log rank analysis. Variables showed statistical significance on survival bz univariate analysis were then put into multivariate Cox-regression analysis. ROC analysis was performed to set the cut off point of certain continuous parameters in relation to survival. The results are summarized on Tables and statistical Figures. Regarding patients mortality in the beginning the main factors with impact were respectively technical ones like arterial thrombosis, while in the last 4 years perioperative fluid management and transfusion policy became important. Both sepsis and postoperative renal insufficiency remained key factors for mortality, however their incidence diminished dramatically. The overall outcome of the retrospective analysis is, that the program has been developed to European standards with respect to its volume, technical capabilities and results.


Quo vadis: tracing the fate of neural crest cells.
The neural crest is a transient structure in vertebrate embryos that produces migratory cells with an astonishing developmental potential. While neural crest fate maps have originally been established through interspecies transplantation assays, dye labeling, and retroviral infection, more recent methods rely on approaches involving transgenesis and genome editing. These technologies allowed the identification of minor neural crest-derived cell populations in tissues of non-neural crest origin. Furthermore, in vivo multipotency at the single cell level and stage-dependent fate acquisitions were demonstrated using genetic technologies. Finally, recent reports indicate that neural crest-derived cells become activated in response to injury to secrete factors supporting tissue repair. Thus, neural crest-derived cells apparently contribute to tissue formation and regeneration by cell autonomous and non-autonomous mechanisms.


Attitudes toward women physicians in medical academia.
To determine attitudes toward women physicians within medical academia, we administered a survey to a probability sample of male and female senior medical students, faculty, and top-level administrators in a randomized, stratified subset of ten medical schools. Of the 984 respondents (65% response rate), men were much less supportive overall than women of female leaders. While women strongly disagreed with the idea that women physicians who spend long hours at work neglect home and family, men were almost equally divided on this issue. Each group rated the "typical" faculty member as "strong, fair, and progressive," but male faculty also were characterized as "egotistical" while female faculty were rated more "sensitive and altruistic." Male students were least likely to support a search for a female dean, hiring more female faculty members, or accepting an incoming class in which the majority were women.


Seeking to understand lived experiences of personal recovery in personality disorder in community and forensic settings - a qualitative methods investigation.
Understandings of personal recovery have emerged as an alternative framework to traditional ideas of clinical progression, or symptom remission, in clinical practice. Most research in this field has focussed on the experience of individuals suffering with psychotic disorders and little research has been conducted to explore the experience of individuals with a personality disorder diagnosis, despite the high prevalence of such difficulties. The nature of the personality disorder diagnosis, together with high prevalence rates in forensic settings, renders the understanding of recovery in these contexts particularly problematic. The current study seeks to map out pertinent themes relating to the recovery process in personality disorder as described by individuals accessing care in either community or forensic settings. Individual qualitative interviews were utilised to explore the lived experience of those receiving a personality disorder diagnosis and accessing mental health care in either community or forensic settings. A thematic analysis was conducted to identify shared concepts and understanding between participants. Fourty-one individual participant interviews were conducted across forensic and community settings. Recovery was presented by participants as a developing negotiated understanding of the self, together with looked for change and hope in the future. Four specific themes emerged in relation to this process: 1. Understanding early lived experience as informing sense of self 2. Developing emotional control 3. Diagnosis as linking understanding and hope for change 4. The role of mental health services. Through considering personal recovery in personality disorder as a negotiated understanding between the individual, their social networks and professionals this study illustrates the complexity of working through such a process. Clarity of understanding in this area is essential to avoid developing resistance in the recovery process. Understanding of recovery in a variety of diagnostic categories and social settings is essential if a truly recovery orientated mental health service is to be developed.


[Computerized tomography of the thorax in intensive care patients].
Thoracic CT for patients in intensive care is cumbersome but provides important additional information in the presence of complicated lung changes. Total opacification of a lung field visualised on conventional portable films may be due to infiltration and/or fluid and/or collapse by using the clinical information in conjunction with densitometric measurements. CT may help in the differentiation of pulmonary oedema, particularly in the presence of ARDS and its complications. It is also possible to accurately localise abscesses and empyemas in the presence of extensive consolidation. This makes it possible to drain abscesses or empyemas, or pleural fluid in unusual situations, which has become loculated, or to aspirate a pneumothorax.


Repurposing Protein Degradation for Optogenetic Modulation of Protein Activities.
Non-neuronal optogenetic approaches empower precise regulation of protein dynamics in live cells but often require target-specific protein engineering. To address this challenge, we developed a generalizable light-modulated protein stabilization system (GLIMPSe) to control the intracellular protein level independent of its functionality. We applied GLIMPSe to control two distinct classes of proteins: mitogen-activated protein kinase phosphatase 3 (MKP3), a negative regulator of the extracellular signal-regulated kinase (ERK) pathway, and a constitutively active form of MEK (CA MEK), a positive regulator of the same pathway. Kinetics study showed that light-induced protein stabilization could be achieved within 30 min of blue light stimulation. GLIMPSe enables target-independent optogenetic control of protein activities and therefore minimizes the systematic variation embedded within different photoactivatable proteins. Overall, GLIMPSe promises to achieve light-mediated post-translational stabilization of a wide array of target proteins in live cells.


Learning to relate images.
A fundamental operation in many vision tasks, including motion understanding, stereopsis, visual odometry, or invariant recognition, is establishing correspondences between images or between images and data from other modalities. Recently, there has been increasing interest in learning to infer correspondences from data using relational, spatiotemporal, and bilinear variants of deep learning methods. These methods use multiplicative interactions between pixels or between features to represent correlation patterns across multiple images. In this paper, we review the recent work on relational feature learning, and we provide an analysis of the role that multiplicative interactions play in learning to encode relations. We also discuss how square-pooling and complex cell models can be viewed as a way to represent multiplicative interactions and thereby as a way to encode relations.


Clinical features in affected males with X-linked retinoschisis.
To assess the phenotypic variation and visual prognosis of affected males with X-linked retinoschisis. Patients were ascertained from clinical geneticists and ophthalmologists in the United Kingdom. Genetic linkage analysis was carried out using polymorphic microsatellite markers from the Xp22 region of the X chromosome. Fifty-six males from 16 British families with X-linked retinoschisis. Best-corrected visual acuity ranged from 20/20 to 20/600; 14 (25%) of the patients saw 20/40 or better, and 27 (55%) read N6 or better. Visual acuity was poorer in older patients (chi 2 =30.4, df=4, P<.001). Macular abnormalities were seen in all eyes. Foveal schisis was the most common abnormality seen in patients younger than 40 years (73 eyes [83%]), but in older patients a blunted foveal reflex or pigmentary atrophy was more common (17 eyes [85%]). Peripheral retinoschisis was seen in 40 (71%) of the patients. Vitreous hemorrhage occurred in 12 (21%) and retinal detachment in nine (16%) of the patients. Four eyes were blind as a result of retinal detachment. Although no evidence exists for genetic heterogeneity in X- linked retinoschisis, there is wide phenotypic variation. The most serious sight-threatening complications are vitreous hemorrhage and retinal detachment. In uncomplicated cases, the prognosis for vision is good, although deterioration of vision occurs in the fourth and fifth decades of life because of macular atrophy.


Motivational interviewing for screening and feedback and encouraging lifestyle changes to reduce relative weight in 4-8 year old children: design of the MInT study.
Because parental recognition of overweight in young children is poor, we need to determine how best to inform parents that their child is overweight in a way that enhances their acceptance and supports motivation for positive change. This study will assess 1) whether weight feedback delivered using motivational interviewing increases parental acceptance of their child's weight status and enhances motivation for behaviour change, and 2) whether a family-based individualised lifestyle intervention, delivered primarily by a MInT mentor with limited support from "expert" consultants in psychology, nutrition and physical activity, can improve weight outcomes after 12 and 24 months in young overweight children, compared with usual care. 1500 children aged 4-8 years will be screened for overweight (height, weight, waist, blood pressure, body composition). Parents will complete questionnaires on feeding practices, physical activity, diet, parenting, motivation for healthy lifestyles, and demographics. Parents of children classified as overweight (BMI > or = CDC 85th) will receive feedback about the results using Motivational interviewing or Usual care. Parental responses to feedback will be assessed two weeks later and participants will be invited into the intervention. Additional baseline measurements (accelerometry, diet, quality of life, child behaviour) will be collected and families will be randomised to Tailored package or Usual care. Parents in the Usual care condition will meet once with an advisor who will offer general advice regarding healthy eating and activity. Parents in the Tailored package condition will attend a single session with an "expert team" (MInT mentor, dietitian, physical activity advisor, clinical psychologist) to identify current challenges for the family, develop tailored goals for change, and plan behavioural strategies that best suit each family. The mentor will continue to provide support to the family via telephone and in-person consultations, decreasing in frequency over the two-year intervention. Outcome measures will be obtained at baseline, 12 and 24 months. This trial offers a unique opportunity to identify effective ways of providing feedback to parents about their child's weight status and to assess the efficacy of a supportive, individualised early intervention to improve weight outcomes in young children. Australian New Zealand Clinical Trials Registry ACTRN12609000749202.


PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy.
The prognostic significance of activity biomarkers within the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway was assessed in two independent cohorts of malignant pleural mesothelioma (MPM) patients uniformly treated with a multimodal approach. We specifically assessed expression signatures in a unique set of pre- and postchemotherapy tumor samples. Biomarker expression was assessed in samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases uniformly treated with platinum-based induction chemotherapy followed by extrapleural pneumonectomy from two different institutions, assembled on tissue microarrays. Expression levels of phosphatase and tensin homologue (PTEN), phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression-free survival (PFS). To assess PTEN genomic status, fluorescence in situ hybridization was performed. Survival analysis showed that high p-S6 and Ki-67 expression in samples of treatment naïve patients of cohort 1 was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples before and after induction chemotherapy of cohort 1 revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression was associated with a worse OAS (p = 0.04 and p = 0.03, respectively). These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.


[Epithelial-stromal interactions in pancreatic adenocarcinoma: the role of stroma in disease progression].
Pancreatic ductal adenocarcinoma (PDAC) is the most common and difficult to treat form of pancreas cancer. PDAC and other solid cancers contain both tumor cells and normal connective tissue cells called stromal cells, which are responsible for the excess production of extracellular matrix. It is known that in more than 90% of PDAC tumors and in many other types of cancer, mutations of the KRAS gene are observed, the reciprocal signaling of which has been shown between tumor and stromal cells in vitro. Pancreatic stromal stellate cells are considered precursors of activated or tumor-associated fibroblasts (CAFs), which are an increasing population of cells that proliferate in situ or are recruited into the tumor. CAFs are a heterogeneous population of stromal fibroblasts with different molecular profiles that change during tumorigenesis. Both immunosuppressive and immunosuppressive subsets of CAFs can coexist in the stroma of a single tumor. Based on the heterogeneity of the intertumor stroma, attempts are being made to classify PDAC and predict the course of the disease.


Molecular typing of enterohemorrhagic Escherichia coli O157:H7 isolates in Japan by using pulsed-field gel electrophoresis.
Pulsed-field gel electrophoresis (PFGE) was applied for molecular typing of 825 enterohemorrhagic Escherichia coli (EHEC) O157:H7 isolates, most of which were from 19 outbreaks and 608 sporadic cases in Japan, mainly in May to August 1996. By PFGE, the EHEC O157:H7 isolates were classified into six types (type I to V and ND [nondescript]) and UT untypeable isolates. Fifty isolates from seven outbreaks in May to June and 60 isolates from patients with sporadic cases of infection showed almost identical PFGE patterns which differed in only 1 of 22 DNA fragments. They were classified into type I. Ninety-nine isolates from 10 other outbreaks and 156 isolates from patients in the Kinki area with sporadic cases of infection obtained in the early summer of 1996 showed identical PFGE patterns, suggesting that they were derived from one huge outbreak. They were classified into type II. Type IV EHEC isolates, which had only the stx2 gene, caused another outbreak in a primary school in June. EHEC isolates of two other types, types III and V, were not related to the outbreak but were isolated in several parts of Japan. ND EHEC isolates included a variety of patterns which could not be classified into either of the types mentioned above. Twenty-five isolates could not be analyzed due to degradation of their genomic DNAs and were represented as UT. These results indicate that EHEC O157:H7 strains with various PFGE types have already spread to Japan and caused the multiple outbreaks and sporadic infections in Japan in the summer of 1996.


Two-year outcomes after sirolimus-eluting stent implantation: results from the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS) trial.
The purpose of this study was to examine the two-year clinical outcomes in patients enrolled in the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) study. The SIRIUS study was a double-blinded randomized study which demonstrated that sirolimus-eluting stents (SES) significantly improved angiographic results (at 8 months) and clinical outcomes (at 9 and 12 months) compared with bare-metal stents (BMS). Patients with de novo native coronary artery lesions randomized to either SES (533 patients) or control BMS (525 patients) were followed for two years. Between one and two years, there were infrequent additional clinical events that were equally distributed between the sirolimus and control groups. After two years, target lesion revascularization was 5.8% and 21.3% in SES and control patients, respectively (p < 0.001), and major adverse cardiovascular events and target vessel failure rates were 10.1% versus 24.4% and 12.0% versus 26.7%, respectively (p < 0.0001 for both). There were no differences in death, myocardial infarction, and stent thrombosis between the two groups. Clinical outcomes two years after implantation of SES continue to demonstrate significant reduction in the need for repeat target lesion (and vessel) revascularization compared with BMS without evidence for either disproportionate late restenosis or late stent thrombosis.


Phylogenetic Comparative Methods for Evaluating the Evolutionary History of Function-Valued Traits.
Phylogenetic comparative methods offer a suite of tools for studying trait evolution. However, most models inherently assume fixed trait values within species. Although some methods can incorporate error around species means, few are capable of accounting for variation driven by environmental or temporal gradients, such as trait responses to abiotic stress or ontogenetic trajectories. Such traits, often referred to as function-valued or infinite-dimensional, are typically expressed as reaction norms, dose-response curves, or time plots and are described by mathematical functions linking independent predictor variables to the trait of interest. Here, I introduce a method for extending ancestral state reconstruction to incorporate function-valued traits in a phylogenetic generalized least squares (PGLS) framework, as well as extensions of this method for testing phylogenetic signal, performing phylogenetic analysis of variance (ANOVA), and testing for correlated trait evolution using recently proposed multivariate PGLS methods. Statistical power of function-valued comparative methods is compared to univariate approaches using data simulations, and the assumptions and challenges of each are discussed in detail.


Kinetics of extracellular ATP hydrolysis by microvascular endothelial cells from rat heart.
We have characterized the ectonucleotidases that catalyse the reaction sequence ATP-->ADP-->AMP-->adenosine on microvascular endothelial cells cultured from the rat heart. Computer simulation and data fitting of progress of reaction curves showed that depletion of substrate at the cell surface dominates the regulation of the rate of hydrolysis of ATP when it is presented to the cells. Preferential delivery of AMP by ADPase to 5'-nucleotidase makes a significant contribution to the regulation of adenosine production from ATP or ADP. By contrast, we found no evidence for the preferential delivery of ADP from ATPase to ADPase. Feed-forward inhibition of AMP hydrolysis by ADP and/or ATP also modulated the rate of adenosine production. The properties of the ectonucleotidases on rat heart microvascular cells are such that adenosine is produced at a steady rate over a wide range of ATP concentrations.


L-leucinthiol - a potent inhibitor of leucine aminopeptidase.
L-leucinthiol (2-amino-4-methyl-1-pentanethiol) was designed as an inhibitor of leucine aminopeptidase by analogy with sulfhydryl inhibitors of other zinc-containing peptidases. It was synthesized from L-leucinol and shown to be a potent competitive inhibitor of the microsomal aminopeptidase from porcine kidney (Ki = 2.2 X 10(-8) M). The results suggest that the mechanism of aminopeptidase may be similar to that of other metalloproteases.


[Comparative studies of atracurium and vecuronium for medium-length surgical procedures in infants and young children].
Onset time, intubation condition and recovery time after single bolus injection of atracurium (0.3 mg/kg in body weight less than 10 kg (Group 1), 0.5 mg/kg in body weight greater than 10 kg (Group 2] and vecuronium (0.05 mg/kg in body weight less than 10 kg (Group 3), 0.1 mg/kg in body weight greater than 10 kg (Group 4] were studied in 40 infants and children anaesthetised with halothane. At the end of the onset time (time from the end of the bolus injection of the muscle relaxant until the maximal twitch depression of the m. adductor pollicis) the intubation conditions were judged as good or very good in both groups. The onset time after bolus injection of atracurium (92.5 +/- 31.9 sec in Group 1, 117.0 +/- 25.2 sec in Group 2) was slightly shorter than after vecuronium (135.7 +/- 64.1 sec in Group 3, 123.3 +/- 26.8 sec in Group 4). The duration from the time of injection to 75% recovery of T1 had been longer by using atracurium (45.2 min in Group 1 + 2) than by vecuronium (36.6 min in Group 3, 34.2 min in Group 4). In infants (Group 1 + 3) the recovery time (duration from 25% to 75% recovery of control twitch height) after relaxation with atracurium as well as vecuronium was longer than in children (Group 2 + 4). Neither cardiovascular side effects nor signs of histamine release occurred after the injection of both muscle relaxants at our dosage level. It is concluded that in infants and children atracurium is a real alternative to vecuronium for relaxation for medium long surgical procedures.(ABSTRACT TRUNCATED AT 250 WORDS)


TEL is a sequence-specific transcriptional repressor.
TEL is a gene frequently involved in specific chromosomal translocations in human leukemia and sarcoma that encodes a member of the ETS family of transcriptional regulators. TEL is unusual among other ETS proteins by its ability to self-associate in vivo, a property that is essential to the oncogenic activation of TEL-derived fusion proteins. We show here that TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven transcription of model and natural promoters. Deletion of the oligomerization domain of TEL or its substitution by the homologous region of monomeric ETS1 impaired the ability of TEL to repress. In contrast, substitution of the oligomerization domain of TEL by unrelated oligomerization domains resulted in an active repressor, showing that the ability of TEL to repress depends on its ability to self-associate. The study of the properties of TEL fusions to the heterologous DNA binding domain of Gal4 identified two autonomous repression domains in TEL, distinct from its oligomerization domain, that are essential to the ability of TEL to repress ETS-binding site-containing promoters. These results have implications for the normal function of TEL, its relation to other ETS proteins, and its role in leukemogenesis.


Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy.
Most human patients with narcolepsy have no detectable hypocretin-1 in their cerebrospinal fluid. The cause of this hypocretin deficiency is unknown, but the prevailing hypothesis states that an autoimmune-mediated mechanism is responsible. We screened for the presence of autoantibodies against neurons in the lateral hypothalamus in 76 patients and 63 controls, using immunohistochemistry. Autoantibodies were present in two patients, but also in two controls. However, one of the patients had a clearly different staining pattern and nerve endings of immunolabeled cells were found to project onto hypocretin-producing neurons, suggesting a possible pathophysiological role. Humoral immune mechanisms appear not to play a role in the pathogenesis of narcolepsy, at least not in the clinically overt stage of the disease.


Clinical Pharmacist Intervention to Engage Older Adults in Reducing Use of Alprazolam.
OBJECTIVE: To assess whether a letter explaining the risks of alprazolam can engage older adults to call a clinical pharmacist (CP) to initiate reduction in alprazolam use. DESIGN: Randomized, controlled study. SETTING: Integrated health care delivery system. PATIENTS: Patients 65 years of age and older who resided at home, had a current supply of alprazolam as of December 15, 2016, and had four outpatient dispensings of alprazolam during the previous 12 months. INTERVENTION: Patients were randomized to receive an educational outreach regarding alprazolam use reduction via a mailed letter (intervention group) or receive usual care (control group). Intervention patients/caregivers were requested to call the CP to discuss reduction of alprazolam use. For intervention patients who called and consented to participate, alternative treatment options were discussed on a case-by-case basis. MAIN OUTCOME MEASURES: Composite rate of 1) no alprazolam dispensing, 2) an alprazolam dose reduction, or 3) interchange to an alternative medication during the six-month follow-up. RESULTS: 153 and 173 patients were and were not, respectively, sent a letter. The mean age was 73 years and patients primarily were female. Thirty (19.6%) intervention patients called the CP. The composite rate was equivalent between the intervention (34.0%) and control (35.3%) groups (P = 0.822). In subanalyses, the composite rate was higher among intervention patients who did vs. those who did not call the CP (77.8% vs. 27.6%; P < 0.001). CONCLUSION: A low-cost patient educational outreach coupled with CP care efficiently engaged older adults in benzodiazepine use reduction process; however, alprazolam continues to be a challenging medication for patients to discontinue.


Pulmonary complications after acute kidney injury.
The development of respiratory failure in patients with AKI is a particularly devastating consequence that greatly increases patient mortality. When respiratory failure and AKI occur together, the mortality is greater than 80%. A clear understanding of the mechanisms leading to respiratory failure is of great clinical relevance to patients with AKI in order to prevent and treat this life-threatening complication. Pulmonary edema leading to respiratory failure has been a recognized complication of kidney failure since 1901. Remarkably, the pathogenesis of this complication remains elusive, despite over 100 years of clinical and experimental debate in the literature. A review of this literature suggests that there are 4 causes of pulmonary edema leading to respiratory failure in patients with AKI: (1) volume overload (cardiogenic edema), (2) left ventricular dysfunction (cardiogenic edema), (3) increased lung capillary permeability (noncardiogenic edema), and (4) acute lung injury (noncardiogenic edema with inflammation). In this review, these mechanisms are presented in historical context including the original descriptions of pathology and pathophysiology, recent epidemiologic data, and experimental studies in animals. Although volume overload is a well-accepted mechanism of pulmonary edema in patients with AKI, the purpose of this review was to highlight the evidence showing that noncardiogenic edema and acute lung injury also occur. By recognizing that the pulmonary complications of AKI are not simply from volume overload, specific treatment strategies may be discovered and used to improve outcomes in patients with the ominous and life threatening combination of AKI and respiratory failure.


Long-Term Health Outcomes of Limb Salvage Compared with Amputation for Combat-Related Trauma.
There are little long-term health data, particularly in terms of body composition and development of metabolic syndromes, to help surgeons to guide the decision between limb salvage and amputation in patients with limb-threatening trauma. The purpose of this study was to compare long-term health outcomes after high-energy lower-extremity trauma between patients who underwent attempted flap-based limb salvage or amputation. We performed a retrospective review of servicemembers with a minimum 10-year follow-up who underwent flap-based limb salvage followed by unilateral amputation or continued limb salvage after combat-related, lower-extremity trauma between 2005 and 2011. Patient demographic characteristics, injury characteristics, and health outcomes including body mass index (BMI) and development of metabolic disease (e.g., hyperlipidemia, hypertension, heart disease, and diabetes) were compared between treatment cohorts. Adjusted BMIs were calculated for the amputation cohort to account for lost surface area. We performed multivariable and propensity score analysis to determine the likelihood of developing obesity or metabolic disease. In this study, 110 patients had available long-term follow-up (mean, 12.2 years) from the time of the injury. Fifty-six patients underwent limb salvage and 54 patients underwent unilateral amputation. There was no difference in preinjury BMI (p = 0.30). After adjusting for limb loss, the amputation cohort had a trend toward higher BMIs at ≥1 years after the injury, a higher rate of obesity, and a greater increase in BMI from baseline after the injury. The development of metabolic comorbidities was common after both amputation (23 [43%] of 54) and limb salvage (27 [48%] of 56). With the numbers available, we were unable to demonstrate a difference in risk for the development of hypertension, hyperlipidemia, diabetes, heart disease, or any comorbidity other than obesity (p > 0.05). Amputations may be medically necessary and may decrease pain, improve mobility, and/or expedite return to activity compared with limb salvage after similar injuries. However, limb loss may negatively impact metabolic regulation and may contribute to a higher risk of obesity despite beneficial effects on mobility. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.


Synthesis and characterization of hexagonal boron nitride used for comparison of removal of anionic and cationic hazardous azo-dye: kinetics and equilibrium studies.
The purpose of this study was to compare the adsorption behavior of cationic and anionic dyes onto a hexagonal boron nitride (hBN) nanostructure that was rich in a negative charge. Herein, the hBN nanostructure was synthesized using boric acid as a precursor material. The characteristic peaks of the hBN nanostructure were performed using Fourier transform infrared (FT-IR) and Raman spectroscopies. The morphology and the particle size of hBN nanostructure were determined by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). During the studies, various essential adsorption parameters were investigated, such as the initial dye concentration, pH of the dye solution, adsorbent dose, and contact time. Under optimal conditions, the removal of 42.6% Metanil yellow (MY) and 90% Victoria blue B (VBB) from aqueous solution was performed using a 10-mg hBN nanostructure. Furthermore, the equilibrium studies showed that the Freundlich isotherm model fitted well for the removal of MY. However, the Langmuir isotherm model fitted well for the removal of VBB. Moreover, according to the results obtained from the kinetic studies, while the first-order kinetic model was suited for the adsorption of the MY, the second-order kinetic model was found to well fit for the adsorption of VBB.


Guidelines for reporting the quality of clinical case reports in Endodontics: a development protocol.
Case reports are used to communicate interesting, new or rare condition/s, innovative treatment approaches or novel techniques. Apart from informing readers, such information has the potential to contribute towards further scientific studies and the development of newer management modalities. In that context, it is important that case reports are presented accurately and deliver all the necessary and pertinent information to the reader. Reporting guidelines are used to inform authors of the quality standards required to ensure their manuscripts are accurate, complete and transparent. The aim of this project is to develop and disseminate new guidelines - Preferred Reporting Items for Case reports in Endodontics (PRICE). The primary aim is to aid authors when constructing case reports in the field of Endodontics to ensure the highest possible reporting standards are adopted. The project leaders (PD and VN) formed a steering committee comprising six additional members. Subsequently, a five-phase consensus process will be used. The steering committee will develop the PRICE guidelines (PRICE checklist and flow chart) by identifying relevant items (quality standards) derived from the CAse REport guidelines and Clinical and Laboratory Images in Publications principles, focussing on the content of case reports. Following this, the steering committee will identify a PRICE Delphi Group (PDG) consisting of 30 members including academicians, practitioners, and members of the public. The individual items (components) of the PRICE checklist will be evaluated by the PDG based on a 9-point Likert scale. Only items scored between 7 and 9 by 70% or more members will be included in the draft checklist. The Delphi process will be continued until a consensus is reached and a final set of items agreed by the PDG members. Following this, a PRICE Face-to-Face meeting group (PFMG) will be formed with 20 members to achieve a final consensus. The final consensus-based checklist and flow chart will be evaluated and approved by selected members of the PDG and PFMG. The approved PRICE guidelines will be published in relevant journals and disseminated via contacts in academic institutions and national endodontic societies, as well as being presented at scientific/clinical meetings.


Extended stability range of the non-Fermi liquid phase in UCoAl.
High pressure was used to investigate the stability of the non-Fermi liquid (NFL) state, observed in electrical resistivity of uranium-based band metamagnet UCoAl in a pure form (paramagnet) or with Fe substitution (ferromagnetic ground state), both in a single-crystal form. By combining the pressure variations of magnetization and resitivity in these materials the phase diagram for UCoAl had been constructed. The band metamagnet transforms into the ferromagnetic state as the critical metamagnetic field is reduced to zero by the lattice expansion analogous to the negative pressure. Within the same diagram, the increasing hydrostatic pressure drives the critical metamagnetic field upwards while reducing the magnetization increment at the transition. The NFL state persists to about 4-5 GPa. Although spin fluctuations play an important role in the character of UCoAl, they do not exhibit any criticality in the sense of divergence of parameters describing the resistivity around the Ferro-NFL phase transition, which is of the first order type.


Patients' preferences over care settings for minor illnesses and injuries.
To identify consumers' preferences over care settings, such as physicians' offices, emergency rooms (ERs), urgent care centers, retail clinics, and virtual physicians on smartphones, for minor illnesses. A survey conducted between 9/27/16 and 12/7/16 emailed to all University of California, Irvine employees. Participants were presented with 10 clinical scenarios and asked to choose the setting in which they wanted to receive care. We estimated multinomial conditional logit regression models, conditioning the choice on out-of-pocket costs, wait time, travel time, and chooser characteristics. 5451 out of 21 037 employees responded. Out-of-pocket costs and wait time had minimal impact on patient's preference for site of care. Choices were driven primarily by the clinical scenario and patient characteristics. For chronic conditions and children's well-visits, the doctor's office was the preferred choice by a strong majority, but for most acute conditions, either the ER (for high severity) or urgent care clinics (for lower severity) were preferred to the office setting, particularly among younger patients and those with less education. Patients have several alternatives to traditional physicians' offices and ERs. The low impact of out-of-pocket costs suggests that insurers interested in encouraging increased utilization of alternatives would need to consider substantial changes to benefit structure.


Schizo-affective psychosis: fact or fiction? A survey of the literature.
The classification of functional psychoses has traditionally been dichotomous with schizophrenia and manic-depressive disorder, which are considered separate entities. However, the psychiatric literature is replete with descriptions of psychoses with mixed features. A variety of names has been applied to these psychoses, including the term "schizo-affective." Confusion exists regarding the nature of these psychoses, much of it resulting from a tendency to limit investigation to an acute view of symptom complexes. This article examines the schizo-affective states across a variety of dimensions, including the acute symptomatologic picture, response to lithium carbonate therapy, follow-up studies, family history, and genetics. While the term "schizo-affective," as commonly used, probably describes a heterogeneous group of psychoses, considerable evidence supports the hypothesis that at least a subgroup of these psychoses has a definite relationship to the major affective disorders.


Characterizing alterations in the pulmonary surfactant system in a rat model of Pseudomonas aeruginosa pneumonia.
Bacterial pneumonia remains a significant cause of patient morbidity and mortality worldwide. Pulmonary surfactant serves to maintain homeostasis in the lung through the maintenance of alveolar stability and the regulation of the alveolar immune response. The purpose of this study was to characterize the lung injury and associated surfactant alterations in a rat model of acute Pseudomonas aeruginosa pneumonia. Pneumonia was induced in male Sprague-Dawley rats via intratracheal injection of 0.2 ml, phosphate-buffered saline (PBS) containing P. aeruginosa (6x10(8) colony-forming units x mL(-1)). Control animals received 0.2 mL sterile PBS. Twenty-four hours after inoculation, the pneumonia group (PN) exhibited clinical signs of pneumonia including deficits in gas exchange, leukopenia and elevated arterial lactate levels. Morphological assessment confirmed the presence of pneumonia with airspaces filled with polymorphonuclear cells. Lung homogenate analysis demonstrated evidence of bacterial colonization of pneumonic lung tissue. Lung compliance was also significantly lower in the PN group. Lung lavage analysis of PN rats revealed the pooled surfactant levels to be lower and the surfactant function reduced compared to control rats. Surfactant composition was also found to be altered in PN rats. These results demonstrate that in Pseudomonas aeruginosa pneumonia, the pulmonary surfactant system is both poorly functioning and reduced in quantity. These alterations may contribute to the lung dysfunction characteristic of this disorder.


Pseudoephedrine-Directed Asymmetric α-Arylation of α-Amino Acid Derivatives.
Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N'-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N'-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.


Will fluctuations in salt marsh-mangrove dominance alter vulnerability of a subtropical wetland to sea-level rise?
To avoid submergence during sea-level rise, coastal wetlands build soil surfaces vertically through accumulation of inorganic sediment and organic matter. At climatic boundaries where mangroves are expanding and replacing salt marsh, wetland capacity to respond to sea-level rise may change. To compare how well mangroves and salt marshes accommodate sea-level rise, we conducted a manipulative field experiment in a subtropical plant community in the subsiding Mississippi River Delta. Experimental plots were established in spatially equivalent positions along creek banks in monospecific stands of Spartina alterniflora (smooth cordgrass) or Avicennia germinans (black mangrove) and in mixed stands containing both species. To examine the effect of disturbance on elevation dynamics, vegetation in half of the plots was subjected to freezing (mangrove) or wrack burial (salt marsh), which caused shoot mortality. Vertical soil development was monitored for 6 years with the surface elevation table-marker horizon system. Comparison of land movement with relative sea-level rise showed that this plant community was experiencing an elevation deficit (i.e., sea level was rising faster than the wetland was building vertically) and was relying on elevation capital (i.e., relative position in the tidal frame) to survive. Although Avicennia plots had more elevation capital, suggesting longer survival, than Spartina or mixed plots, vegetation type had no effect on rates of accretion, vertical movement in root and sub-root zones, or net elevation change. Thus, these salt marsh and mangrove assemblages were accreting sediment and building vertically at equivalent rates. Small-scale disturbance of the plant canopy also had no effect on elevation trajectories-contrary to work in peat-forming wetlands showing elevation responses to changes in plant productivity. The findings indicate that in this deltaic setting with strong physical influences controlling elevation (sediment accretion, subsidence), mangrove replacement of salt marsh, with or without disturbance, will not necessarily alter vulnerability to sea-level rise.


Integrating gender perspectives in gynecology and obstetrics: Engaging medical colleges in Maharashtra, India.
Failure to acknowledge the impact of sex and gender differences affects the quality of health care provision, and is an impediment to reducing health inequities. Systematic efforts were initiated in Maharashtra, India for reducing these disparities by developing gender-integrated curricula in undergraduate (UG) medical education between 2015 and 2018. A review of UG obstetrics and gynecology curricula indicated a lack of gender lens and focus on the reproductive rights of women. Based on these gaps, a gender-integrated curriculum was developed, implemented, and tested with medical students. Significant positive attitudes were seen among male and female students for themes such as access to safe abortion; understanding reproductive health concerns and their complex relationship with gender roles; violence against women as a health issue; and sexuality and health. These results strengthened the resolve to advocate for such a curriculum to be integrated across all medical colleges in the state.


The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass.
The FoxM1 transcription factor is highly expressed in proliferating cells and activates several cell cycle genes, although its requirement appears to be limited to certain tissue types. Embryonic hepatoblast-specific inactivation of Foxm1 results in a dramatic reduction in liver outgrowth and subsequent late gestation lethality, whereas inactivation of Foxm1 in adult liver impairs regeneration after partial hepatectomy. These results prompted us to examine whether FoxM1 functions similarly in embryonic outgrowth of the pancreas and beta-cell proliferation in the adult. We found that FoxM1 is highly expressed in embryonic and neonatal endocrine cells, when many of these cells are proliferating. Using a Cre-lox strategy, we generated mice in which Foxm1 was inactivated throughout the developing pancreatic endoderm by embryonic d 15.5 (Foxm1(Deltapanc)). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and beta-cell mass; however, they displayed a gradual decline in beta-cell mass with age. Failure of postnatal beta-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in beta-cell mass in Foxm1(Deltapanc) animals is due to a dramatic decrease in postnatal beta-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27(Kip1), a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal beta-cell mass and regulate postnatal beta-cell turnover. These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population.


Association between baseline psychological attributes and mental health outcomes after soldiers returned from deployment.
Psychological health is vital for effective employees, especially in stressful occupations like military and public safety sectors. Yet, until recently little empirical work has made the link between requisite psychological resources and important mental health outcomes across time in those sectors. In this study we explore the association between 14 baseline psychological health attributes (such as adaptability, coping ability, optimism) and mental health outcomes following exposure to combat deployment. Retrospective analysis of all U.S. Army soldiers who enlisted between 2009 and 2012 and took the Global Assessment Tools (GAT) before their first deployment (n = 63,186). We analyze whether a soldier screened positive for depression and posttraumatic stress disorder (PTSD) after returning from deployment using logistic regressions. Our key independent variables are 14 psychological attributes based on GAT, and we control for relevant demographic and service characteristics. In addition, we generate a composite risk score for each soldier based on the predicted probabilities from the above multivariate model using just baseline psychological attributes and demographic information. Comparing those who scored in the bottom 5 percentile of each attribute to those in the top 95 percentile, the odds ratio of post-deployment depression symptoms ranges from 1.21 (95% CI 1.06, 1.40) for organizational trust to 1.73 (CI 1.52, 1.97) for baseline depression. The odds ratio of positive screening of PTSD symptoms ranges from 1.22 for family support (CI 1.08, 1.38) to 1.51 for baseline depression (CI 1.32, 1.73). The risk profile analysis shows that 31% of those who screened positive for depression and 27% of those who screened positive for PTSD were concentrated among the top 5% high risk population. A set of validated, self-reported questions administered early in a soldier's career can predict future mental health problems, and can be used to improve workforce fit and provide significant financial benefits to organizations that do so.


The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A.
The heterotetrameric adaptor protein complex 4 (AP-4) is a component of a protein coat associated with the trans-Golgi network (TGN). Mutations in AP-4 subunits cause a complicated form of autosomal-recessive hereditary spastic paraplegia termed AP-4-deficiency syndrome. Recent studies showed that AP-4 mediates export of the transmembrane autophagy protein ATG9A from the TGN to preautophagosomal structures. To identify additional proteins that cooperate with AP-4 in ATG9A trafficking, we performed affinity purification-mass spectrometry followed by validation of the hits by biochemical and functional analyses. This approach resulted in the identification of the fused toes homolog-Hook-FHIP (FHF) complex as a novel AP-4 accessory factor. We found that the AP-4-FHF interaction is mediated by direct binding of the AP-4 μ4 subunit to coiled-coil domains in the Hook1 and Hook2 subunits of FHF. Knockdown of FHF subunits resulted in dispersal of AP-4 and ATG9A from the perinuclear region of the cell, consistent with the previously demonstrated role of the FHF complex in coupling organelles to the microtubule (MT) retrograde motor dynein-dynactin. These findings thus uncover an additional mechanism for the distribution of ATG9A within cells and provide further evidence for a role of protein coats in coupling transport vesicles to MT motors.


Peripartum anesthetic management of patients with Factor XI deficiency.
Factor XI deficiency is predominantly found in the Ashkenazi Jewish population with a prevalence of 9%, but also seen in other ethnicities. Little information is available on obstetric anesthesia management in women with Factor XI deficiency. Therefore, we undertook a study to evaluate obstetric, anesthetic and perinatal outcomes in parturients with Factor XI deficiency. A retrospective study was conducted with chart reviews from 1996 to 2011 resulted in 74 women with Factor XI level deficiency. We compared anesthetic and obstetric management in parturients with low (≤30%) level of Factor XI to those with higher levels. Ninety-one pregnancy outcomes were reviewed in these 74 women with Factor XI deficiency. Forty-three women had levels ≤30% in 46 labors while 31 women had levels >30% in 45 labors. Women with low levels of Factor XI were significantly more likely to receive FFP and less likely to receive neuroaxial anesthesia. There were no anesthetic complications and no difference in mode of delivery or neonatal outcomes. This study is the first step in building a national database for anesthetic cases and outcomes of parturients with Factor XI deficiency. Further efforts must be made to provide safe analgesia for these women.


Difficult complications after hip joint replacement. Dislocation.
Dislocation after hip replacement occurs at an overall incidence of 2% to 3% and has significant cost and morbidity implications. Statistically increased incidence is observed in females and in the elderly, and after reoperation procedures. Specific causes include cup malrotation, trochanteric migration, and decreased femoral offset. Head size, leg length, and postoperative mobilization have not proven to be causative factors, but the posterior exposure statistically and consistently is associated with increased instability. Extended acetabular walls do lessen the incidence of dislocation in the primary but even more significantly in the revision procedure. Early (< 3 months) dislocations successfully are treated by 4 to 8 weeks of immobilization in 60% to 70% of instances. The most successful reoperations are those in which the specific cause of the dislocation has been defined. The success rate is approximately 80% for cup reorientation and trochanteric advancement. Nonspecific or ill defined causes are managed successfully by surgical intervention in only approximately 50% of cases. With extensive soft tissue compromise, limited experience with certain salvage options include the bipolar implant with a reported success rate of approximately 80%. Captive articular designs also seem to be successful in approximately 70% of instances but with relatively short term followup and lingering concerns regarding the long term integrity of the fixation.


What can associative learning do for planning?
There is a new associative learning paradox. The power of associative learning for producing flexible behaviour in non-human animals is downplayed or ignored by researchers in animal cognition, whereas artificial intelligence research shows that associative learning models can beat humans in chess. One phenomenon in which associative learning often is ruled out as an explanation for animal behaviour is flexible planning. However, planning studies have been criticized and questions have been raised regarding both methodological validity and interpretations of results. Due to the power of associative learning and the uncertainty of what causes planning behaviour in non-human animals, I explored what associative learning can do for planning. A previously published sequence learning model which combines Pavlovian and instrumental conditioning was used to simulate two planning studies, namely Mulcahy & Call 2006 'Apes save tools for future use.' Science 312, 1038-1040 and Kabadayi & Osvath 2017 'Ravens parallel great apes in flexible planning for tool-use and bartering.' Science 357, 202-204. Simulations show that behaviour matching current definitions of flexible planning can emerge through associative learning. Through conditioned reinforcement, the learning model gives rise to planning behaviour by learning that a behaviour towards a current stimulus will produce high value food at a later stage; it can make decisions about future states not within current sensory scope. The simulations tracked key patterns both between and within studies. It is concluded that one cannot rule out that these studies of flexible planning in apes and corvids can be completely accounted for by associative learning. Future empirical studies of flexible planning in non-human animals can benefit from theoretical developments within artificial intelligence and animal learning.