In vitro synergy of sertraline and tetracycline cannot be reproduced in pigs orally challenged with a tetracycline resistant Escherichia coli.
Antimicrobial helper-compounds may reverse antimicrobial resistance. Sertraline, a antidepressant drug, has been suggested as a tetracycline helper-compound. Tetracycline is the preferred antimicrobial for treatment of enteric diseases in pigs. This study is the first to evaluate the potency of sertraline as a tetracycline adjuvant in pigs. Forty-eight nursery pigs were divided into four treatment groups: Tetracycline, sertraline, tetracycline/sertraline or un-medicated control. Fecal and ileal samples were obtained before treatment, 48 h and nine days after five days of treatment, respectively. Colony forming units (CFU) of tetracycline resistant coliforms in each sample (ileal or fecal) and CFU of an orally inoculated tetracycline-resistant strain of Escherichia coli were determined at each sampling point. The microbiome of fecal and ileal and samples was analyzed by sequencing of the 16S V3-V4 region. The results did not provide evidence that sertraline in combination with tetracycline has any impact on tetracycline resistant bacteria in either fecal or ileum samples, while in the tetracycline treated group of pigs, an increase in the prevalence of a tetracycline resistant indicator strain of Escherichia coli shortly after ended five-day treatment was observed. The ileal samples obtained shortly after ended treatment showed treatment-associated changes in the composition of the microbiota in the groups of pigs treated with tetracycline (+/-) sertraline. While tetracycline treatment increased the abundance in the reads of E. coli, sertraline/tetracycline treatment led to increased abundances of Streptococcus spp. and decreased abundances of Lactobacillus spp. However, all observed differences (on CFU counts and microbiota composition) between groups shortly after treatment had diminished in less than two weeks after last treatment day. Sertraline (+/-) tetracycline treatment did not reduce the long-term level of tetracycline-resistant bacteria in the feces or small intestine contents of piglets compared to the un-medicated control group of pigs. The result of this study reflects the importance of in vivo studies for confirmation of the antimicrobial helper-compound potential of an in vitro active compound.


Size frequency distribution of martian craters and relative age of light and dark terrains.
Light and dark terrains in and around Meridiani Sinus, mapped on the imagery from Mariner 6 and Mariner 7, were found to have significantly different cumulative size frequency distributions of craters. The light terrain on a mosaic of frames 6N11, 6N13, and 6N19 has a greater proportion of large craters and a lesser proportion of smaller craters than the dark terrain on the same frames. The light terrain is interpreted to be generally older than the dark terrain. The filling or partial filling of the smaller craters on the light terrain by surface detritus is suggested. Several wide-angle frames have remarkably similar cumulative crater size frequency distributions that may be representative of a large portion of the martian surface.


Evaluation and early detection of problematic Internet use in adolescents.
Problematic Internet use in adolescents has become an issue of concern for a growing number of researchers and institutions over the past years. Behavioural problems, social isolation, school failure and family problems are some of the consequences of psychological and behavioural impact on teenagers. Taking into account the interest that this issue has generated at many levels, the aim of this paper is to develop a screening tool for early detection of problematic Internet use in teenagers. A survey of Compulsory Secondary School students from Galicia involving a total of 2,339 individuals was carried out. The results obtained allow (1) gauging the magnitude of the problem, establishing the risk levels among the adolescents, and (2) presenting a new, simple and short screening instrument. The present scale has sufficient theoretical and empirical support, including good psychometric properties (a = .83; specificity = .81; sensitivity = .80; ROC curve = .90), making it an interesting applied tool.


[Epileptic seizures in patients with systemic rheumatic disorders].
Systemic rheumatic disorders affect multiple organ systems. Seizures are among the most common neurological manifestation and occasionally can be the presenting symptom. This article reviews the literature on the mechanisms underlying seizures in systemic rheumatic disorders and predisposing factors, including vascular disease (e.g., prothrombotic state, anticardiolipin antibody, emboli, vasculitis), antineuronal antibodies, immune complexes, cytokines, metabolic disorders, infection, and therapy. Diagnostic and therapeutic strategies must be individualized for both the disorder and the patient.


Probing the repulsive core of the nucleon-nucleon interaction via the (4)He(e,e'pN) triple-coincidence reaction.
We studied simultaneously the (4)He(e,e'p), (4)He(e,e'pp), and (4)He(e,e'pn) reactions at Q(2)=2(GeV/c)(2) and x(B)>1, for an (e,e'p) missing-momentum range of 400 to 830 MeV/c. The knocked-out proton was detected in coincidence with a proton or neutron recoiling almost back to back to the missing momentum, leaving the residual A=2 system at low excitation energy. These data were used to identify two-nucleon short-range correlated pairs and to deduce their isospin structure as a function of missing momentum, in a region where the nucleon-nucleon (NN) force is expected to change from predominantly tensor to repulsive. The abundance of neutron-proton pairs is reduced as the nucleon momentum increases beyond ∼500 MeV/c. The extracted fraction of proton-proton pairs is small and almost independent of the missing momentum. Our data are compared with calculations of two-nucleon momentum distributions in (4)He and discussed in the context of probing the elusive repulsive component of the NN force.


Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice.
The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet-fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element-like elements and one sterol regulatory element (SRE)-binding site within a -2,468 ∼+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c-induced Thrsp transcription. Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α-mediated, SREBP-1c-dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD.


Familial tendency and risk of nasopharyngeal carcinoma in taiwan: effects of covariates on risk.
In the present study, the authors compared the long-term risk of nasopharyngeal carcinoma (NPC) of male participants in an NPC multiplex family cohort with that of controls in a community cohort in Taiwan after adjustment for anti-Epstein-Barr virus (EBV) seromarkers and cigarette smoking. A total of 43 incident NPC cases were identified from the 1,019 males in the NPC multiplex family cohort and the 9,622 males in the community cohort, for a total of 8,061 person-years and 185,587 person-years, respectively. The adjusted hazard ratio was 6.8 (95% confidence interval (CI): 2.3, 20.1) for the multiplex family cohort compared with the community cohort. In the evaluation of anti-EBV viral capsid antigen immunoglobulin A and anti-EBV deoxyribonuclease, the adjusted hazard ratios were 2.8 (95% CI: 1.3, 6.0) and 15.1 (95% CI: 4.2, 54.1) for those positive for 1 EBV seromarker and positive for both seromarkers, respectively, compared with those negative for both EBV seromarkers. The adjusted hazard ratio was 31.0 (95% CI: 9.7, 98.7) for participants who reported a family history of NPC and who were anti-EBV-seropositive compared with individuals without such a history who were anti-EBV-seronegative. The findings suggest that both family history of NPC and anti-EBV seropositivity are important determinants of subsequent NPC risk and that the effect of family history on NPC risk cannot be fully explained by mediation through EBV serologic responses.


Racial Disparity and Triple-Negative Breast Cancer in African-American Women: A Multifaceted Affair between Obesity, Biology, and Socioeconomic Determinants.
Triple negative breast cancer (TNBC) is a molecularly heterogeneous disease whose incidence is disproportionately higher in African American (AA) women compared to European American (EA) women. Earlier onset, more advanced stage at diagnosis, and aggressive tumor phenotype are some of the characteristic features of TNBC in women with African ethnicity in comparison to EA women, denoting one of the most significant examples of racial disparity in oncology. It is still contentious whether health disparities result in aggressive behavior of TNBC in AA women or it is indeed a molecularly distinct disease. Given the "gaps-in-knowledge" surrounding racial disparity in TNBC, this review discusses various socioeconomic factors and the genetic predispositions contributing to poor prognosis of TNBC in AA women. While socioeconomic factors may contribute to poorer survival, multiple preclinical and clinical studies suggest inherent genetic risk factors and aberrant activation of oncogenic pathways in AA TNBC. Additionally, AA women are more likely to be obese and obesity is known to drive a molecular circuitry resulting in aggressive tumor progression indicating a potential obesity-TNBC axis at work in AA women. Given the multifactorial nature of AA TNBC, a transdisciplinary approach may help bridge the disparity that exists between AA and EA TNBC.


Drug wanting: behavioral sensitization and relapse to drug-seeking behavior.
Repeated exposure to drugs of abuse enhances the motor-stimulant response to these drugs, a phenomenon termed behavioral sensitization. Animals that are extinguished from self-administration training readily relapse to drug, conditioned cue, or stress priming. The involvement of sensitization in reinstated drug-seeking behavior remains controversial. This review describes sensitization and reinstated drug seeking as behavioral events, and the neural circuitry, neurochemistry, and neuropharmacology underlying both behavioral models will be described, compared, and contrasted. It seems that although sensitization and reinstatement involve overlapping circuitry and neurotransmitter and receptor systems, the role of sensitization in reinstatement remains ill-defined. Nevertheless, it is argued that sensitization remains a useful model for determining the neural basis of addiction, and an example is provided in which data from sensitization studies led to potential pharmacotherapies that have been tested in animal models of relapse and in human addicts.


Quality of life and mild cognitive impairment in early Parkinson's disease: does subtype matter?
We evaluated the association between mild cognitive impairment (MCI) subtypes and quality of life (QoL) in 219 newly diagnosed Parkinson's disease (PD) patients without dementia. Participants completed neuropsychological tests of attention, executive function, visuospatial function, memory, and language, and reported QoL using the Parkinson's Disease Questionnaire. Impairments were most common in executive function, memory and attention. MCI subtypes were classified according to Movement Disorder Society Task Force criteria. More severe cognitive impairment was associated with poorer quality of life (p = 0.01), but subtype of impairment was not (p > 0.10), suggesting that the nature of cognitive impairment is less significant than its severity.


Quasispecies Changes with Distinctive Point Mutations in the Hepatitis C Virus Internal Ribosome Entry Site (IRES) Derived from PBMCs and Plasma.
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome contains the internal ribosome entry site (IRES), a highly conserved RNA structure essential for cap-independent translation of the viral polyprotein. HCV, apart from the liver, is thought to be associated with lymphocyte subpopulations of peripheral blood mononuclear cells (PBMCs), in lymph nodes and brain tissue. In this study, RT-PCR, cloning, and sequence analysis were employed to investigate the quasispecies nature of the 5'UTR following extraction of viral RNA from PBMCs and plasma of HCV infected individuals. The nucleotide variation between IRES-derived sequences from PBMCs and plasma indicated the existence of polymorphic sites within the IRES. HCV isolates had divergent variants with unique mutations particularly at positions 107, 204, and 243 of the IRES. Most of the PBMC-derived sequences contained an A-A-A variant at these positions. The mutations associated with the IRESes suggested the presence of unique quasispecies populations in PBMCs compared with plasma.


Insights from the Den: How Hibernating Bears May Help Us Understand and Treat Human Disease.
Hibernating brown bears (Ursus arctos) and black bears (Ursus americanus) spend half of the year in a physically inactive state inside their winter dens without food intake and defecating and no or little urination. Under similar extreme conditions, humans would suffer from loss of lean body mass, heart failure, thrombosis, azotemia, osteoporosis, and more. However, bears exit the den in the spring strong without organ injuries. Translational animal models are used in human medicine but traditional experimental animals have several shortcomings; thus, we believe that it is time to systematically explore new models. In this review paper, we describe physiological adaptations of hibernating bears and how similar adaptations in humans could theoretically alleviate medical conditions. The bear has solved most of the health challenges faced by humans, including heart and kidney disease, atherosclerosis and thrombosis, and muscle wasting and osteoporosis. Understanding and applying this library of information could lead to a number of major discoveries that could have implications for the understanding and treatment of human disease.


Hierarchical neighbor effects on mycorrhizal community structure and function.
Theory predicts that neighboring communities can shape one another's composition and function, for example, through the exchange of member species. However, empirical tests of the directionality and strength of these effects are rare. We determined the effects of neighboring communities on one another through experimental manipulation of a plant-fungal model system. We first established distinct ectomycorrhizal fungal communities on Douglas-fir seedlings that were initially grown in three soil environments. We then transplanted seedlings and mycorrhizal communities in a fully factorial experiment designed to quantify the direction and strength of neighbor effects by focusing on changes in fungal community species composition and implications for seedling growth (a proxy for community function). We found that neighbor effects on the composition and function of adjacent communities follow a dominance hierarchy. Specifically, mycorrhizal communities established from soils collected in Douglas-fir plantations were both the least sensitive to neighbor effects, and exerted the strongest influence on their neighbors by driving convergence in neighbor community composition and increasing neighbor seedling vigor. These results demonstrate that asymmetric neighbor effects mediated by ecological history can determine both community composition and function.


Impaired beta-adrenergically mediated lipolysis in skeletal muscle of obese subjects.
The aim of this study was to investigate whether the beta2-adrenergically mediated increase in interstitial glycerol concentrations (used as an indicator of local lipolysis) was impaired in the skeletal muscle (the gastrocnemius muscle) of obese subjects compared with in that of lean subjects, and whether any differences in muscle lipolysis were related to differences in intramyocellular muscle triglyceride content. A microdialysis experiment was performed in the gastrocnemius muscle of eight lean and eight obese men (body fat 22.1+/-1.6% vs 32.7+/-1.6% respectively). After determining baseline extracellular glycerol concentrations, the probe was perfused with increasing concentrations of the beta2-agonist, salbutamol (doses of 1, 10 and 100 micromol/l for 45-min periods). Local blood flow was determined using the ethanol dilution technique. Intramyocellular lipid content was determined using 1H-magnetic resonance spectroscopy. Compared with that in lean subjects, the beta2-adrenergically mediated increase in glycerol concentrations (absolute and percentage change) was blunted in obese subjects (at 100 micromol/l of salbutamol, percentage change 12.0+/-12% vs 48+/-12%, p<0.05). The decrease in ethanol out:in ratio was less pronounced in the obese individuals ( p<0.05), indicating a diminished increase in local muscle blood flow. Intramyocellular lipid content was comparable in both groups. The capacity to increase skeletal interstitial glycerol concentrations during direct beta2-adrenergic stimulation is impaired in obese subjects with normal intramyocellular concentrations, suggesting that this may be an early event in the process of triglyceride accumulation.


Analysis of neonatally induced tolerance of H-2 alloantigens. I. Adoptive transfer indicates that tolerance of class I and class II antigens is maintained by distinct mechanisms.
Neonatal inoculation of mice with semi-allogeneic lymphohematopoietic cells produces a state of highly specific allograft tolerance. Phenotypically, by both in vivo and in vitro criteria, antigen-reactive cells specific for the tolerated antigens appear to be clonally deleted from intact, tolerant mice. However, a series of adoptive transfer experiments using mice rendered tolerant of various H-2 alloantigens revealed that tolerance of Ia (class II) antigens is maintained by a different mechanism than tolerance of K/D (class I) antigens. Long-term acceptance of Ia-disparate grafts by recipients of Ia-tolerant lymphoid cells suggested that an active process (rather than passive clonal deletion) mediates and maintains this type of tolerance. No comparable success was achieved when tolerance of isolated class I or entire H-2 haplotype disparity was examined, suggesting that clonal deletion might be operative in these combinations. Modest prolongation of skin-graft survival was observed in adoptive transfer recipients of lymphoid cells from donors tolerant of I-JECSD disparity. These data are compatible with the hypothesis that the central I region (JE) promotes tolerance induction to associated strong IA- and D-region alloantigens by activating a suppression mechanism.


Treatment in typical and atypical rolandic epilepsy.
Benign rolandic epilepsy is the most common epilepsy of childhood. Regarding seizure control typical and atypical rolandic epilepsies have a reasonable prognosis. In a recent prospective study STM was shown to control seizures in BECTS and STM is regarded as first line drug for this epilepsy in countries having access to this drug. Otherwise, CBZ is used most often and very effectively in BECTS. However, CBZ has the disadvantage to worsen clinical and EEG features up to the precipitation of CSWS in few patients. Epileptic seizures are often not the main problem in atypical rolandic epilepsies like CSWS or LKS and the amelioration of cognitive dysfunction by epileptic discharge is the prominent aim of an AED therapy. Steroids seem the have the best efficacy in these cases.


Association between health-related quality of life and heart rate variability in elderly individuals with cognitive impairment in Korea: cross-sectional study.
Cognitive impairment, a characteristic and prior stage of dementia, is a serious public health concern in Korea a country with rapidly aging population. In a neurovisceral integration model, cognitive ability is connected to emotional and autonomic regulation via an interconnection in the brain, which may be associated with health-related quality of life (HRQoL). This study investigated the association between the HRQoL and the autonomic nervous system (ANS) via EuroQoL-5 Dimension (EQ-5D) and heart rate variability (HRV) among 417 patients who visited the Neurology Department in Veterans Health Service Medical Center, Seoul, South Korea. The mean age of 275 patients in the cognitive impairment group (CIG) was higher than that of 142 patients in the normal cognition group (NCG) (74.85 years vs. 72.96 years, p < 0.001). In a generalized linear model with a beta coefficient (β), an increase in HRQoL was associated with higher HRV levels was observed only in CIG (CIG: the standard deviation of all NN intervals (SDNN) (ln, ms): β = 0.02, p = 0.007; Total power spectral density (TP) (ln, ms2): β = 0.01, p = 0.007; High frequency (HF) (ln, ms2): β = 0.01, p = 0.015; Low frequency (LF) (ln, ms2): β = 0.01, p = 0.003) (NCG: SDNN (ln, ms): β = 0.01, p = 0.214; TP (ln, ms2): β = 0.01, p = 0.144; HF (ln, ms2): β = 0.00, p = 0.249; LF (ln, ms2): β = 0.01, p = 0.294). We found a significant association between HRQoL and HRV in Korean elders with cognitive impairment. However, this study is cross-sectional, so we cannot define direct causation. Further studies are needed to support our findings and to elucidate the biological mechanisms underlying these associations, especially in people cognitively impaired.


[The prognostic value of evaluation of minimal residual disease using technique of flow cytofluorometry during application of therapy of chronic lymphatic leukemia].
The achievement of molecular remission is associated with increasing of survival of patients with chronic lymphatic leukemia. The important direction of research is seeking of parameters applicable to forecast of response to therapy. The purpose of the study was evaluating prognostic significance of indicator of minimal residual disease detected by technique of flow cytofluorometry of peripheral blood of patients with chronic lymphatic leukemia during therapy application. The sampling included 112 patients with chronic lymphatic leukemia aged from 43 to 82 years. All patients were given treatment consisted of 6 courses of immune chemotherapy combined with fludarabine with cyclophosphan and rituximab. The samples of peripheral blood were analyzed after 3 courses during therapy and after 6 courses after completion of treatment. The cells were analyzed using 5 and 6 color flow cytometry for the purpose of detection of immune phenotype associated with chronic lymphatic leukemia. The evaluation of minimal residual disease was implemented according international standardized protocol (Rawstron A.C. et al. 2007; 21 (5): 956-64). The minimal residual disease negative status was reached in 87 (78%) patients during evaluation of response after 6th course of treatment. The implementation of indicators of residual disease after 3 courses with fludarabine, cyclophosphan and rituximab permitted to sort out two groups of patients with chronic lymphatic leukemia i.e 67 patients with low (< 0.12%) level of minimal residual disease and 45 patients with high (> 0.12%) level of tumor cells. The rate of molecular remission after completion of treatment. in the given groups consisted 100% and 44% correspondingly. The study demonstrates possibilities of early immune phenotype evaluation of minimal residual disease to forecast differences in response to treatment in patients with chronic lymphatic leukemia that makes it possible to avoid undesirable toxicity of therapy or to choose method of consolidation.


Quantitative analysis of immunosuppression in cyclosporine-treated heart transplant patients with lymphoma.
Lymphoma remains an important complication after heart transplantation in the era of cyclosporine immunosuppression. It has been generally assumed that the occurrence of lymphoma related to quantitative degree of immunosuppression, and this assumption is exemplified in the treatment of some such lymphomas with reduction of immunosuppression. Seventy-five consecutive survivors of heart and heart-lung transplantation between December 1980 and July 1983 were treated with cyclosporine and steroids; some received rabbit anti-thymocyte globulin for prophylaxis or treatment of rejection. Measured quantitative parameters of immunosuppression during the first three months after transplantation included mean cyclosporine level, total rabbit anti-thymocyte globulin dosage, number of days of T-cell suppression, and mean cyclosporine level during T-cell suppression. Serial Epstein-Barr virus antibody titers were measured. Lymphoma was diagnosed in six patients. The mean number of episodes of rejection did not differ between the lymphoma and the non-lymphoma groups. All quantitative measures of immunosuppression were higher in the lymphoma group, but this difference achieved statistical significance only in the case of total dosage of rabbit anti-thymocyte globulin (p less than 0.02). Four of the six lymphoma patients received some or all of their rabbit anti-thymocyte globulin dosage as prophylaxis against rejection; one received rabbit anti-thymocyte globulin solely for rejection; and the sixth received no rabbit anti-thymocyte globulin. Ebstein-Barr virus titer conversion (four-fold rise in titer) alone was not significantly associated with occurrence of lymphoma. However, logistic regression analysis suggested that Epstein-Barr virus conversion in concurrence with high mean cyclosporine levels predicted a higher risk of lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)


Exercise-induced bronchoconstriction does not cause eosinophilic airway inflammation or airway hyperresponsiveness in subjects with asthma.
The cysteinyl leukotrienes (LT) C(4), D(4), and E(4) may partially mediate eosinophilic airway inflammation in patients with asthma. High- intensity exercise by patients with asthma can result in exercise- induced bronchoconstriction, partly due to leukotriene production, but it is still debated whether this causes airway inflammation. Ten subjects completed a randomized, controlled study to examine the effects of exercise-induced bronchoconstriction on airway inflammatory cells. Subjects completed exercise challenge and methacholine challenge in random order separated by 1 wk. Spirometry was measured for 2 h after challenges, and airway responsiveness was measured the day before and 24 h after each challenge. Blood and sputum samples were obtained before, and 2, 4, 7, and 24 h after each challenge for measurement of inflammatory cells. Nine of the subjects inhaled allergen at least 3 wk before or 1 wk after the study. Sputum samples were collected before, 7 h, and 24 h after challenge. The maximum percentage fall in FEV(1) was 21.3 +/- 1.5% after exercise, 29.9 +/- 1.5% after methacholine, and 28.9+/-2.7% after allergen. Exercise had no effect on airway responsiveness or inflammatory cells measured in blood or sputum, unlike allergen inhalation, which resulted in significant airway hyperresponsiveness and increases in sputum eosinophils (p < 0.05). This study demonstrates that exercise-induced bronchoconstriction does not cause eosinophilic airway inflammation in subjects with asthma who develop airway inflammation with the same degree of allergen-induced bronchoconstriction. We conclude that exercise-induced bronchoconstriction does not cause airway inflammation or airway hyperresponsiveness.


[Advanced nurse triage for emergency department].
To cope with overcrowding, a consequence of their constant growth, emergency departments have implemented operational strategies based on triage systems. Despite its interest, nurse triage has been limited by several hindrances, and new strategies are emerging. Among those, advanced nurse triage, allowing a nurse to initiate the diagnostic process just after categorization of the patient, seems to be promising. A study on advanced nurse triage for patients presenting with chest pain has been conducted in the emergency department of the CHU of Liège. The encouraging results obtained following this new system demonstrate a reduction of the delay to management of patients, and a reduction of the total length of stay in the emergency unit mainly during overcrowding periods. Advanced nurse triage, in addition to a conventional triage during overcrowding periods, improves management of patients in terms of time and reduces the total time spent in the emergency department.


Menouria due to congenital vesicovaginal fistula associated with complex genitourinary malformation.
Congenital vesicovaginal fistula (VVF) is a very uncommon condition rarely suspected at initial presentation. It is usually seen in association with complex malformations of the genitourinary tract. A bifid insertion of the solitary ureter causing an uretero-VVF was associated with an obstructing transverse vaginal septum manifesting as menouria. Also seen were solitary crossed renal ectopia, bicornuate uterus and skeletal anomalies. In women with menouria without vaginal menstruation, pre-operative evaluation to detect an obstructive vaginal anomaly and unusual uretero-vesicovaginal fistulous communications is necessary before surgical intervention.


Anti-biofouling Sulfobetaine Polymer Thin Films on Silicon and Silicon Nanopore Membranes.
Silicon nanopore membranes (SNM) with monodisperse pore size distributions have potential applications in bioartificial kidneys. A protein resistant thin film coating on the SNM is required to minimize biofouling and, hence, enhance the performance efficiency of SNM. In this work, a zwitterionic polymer, poly(sulfobetaine methacrylate) (polySBMA), was used to coat silicon and SNM substrates via a surface initiated atom transfer radical polymerization method. The polySBMA-coated surfaces were characterized using contact angle goniometry, X-ray photoelectron spectroscopy (XPS), ellipsometry and scanning electron microscopy (SEM). Resistance of the coatings to protein fouling was examined by measurement of fibrinogen adsorption from fibrinogen solution and human plasma on coated silicon surfaces. Results showed that the polySBMA coating suppresses non-specific adsorption of fibrinogen. The protein-repellent property of polySBMA thin film coating is comparable to that of PEG-based coatings. Analysis of the surfaces by XPS indicated that the films remained stable when stored under physiologic conditions over a 4-week period.


Biologic treatments for severe asthma: 4 year experience of a single medical center.
Severe asthma affects up to 20,000 citizens of Israel. Novel biological therapies, which individually have been proven to reduce asthma morbidity in clinical trials, have become available in recent years. Comparative data among different drugs are scarce. To describe and compare the clinical outcomes of biological therapies in severe asthma patients treated at Shamir Medical Center. We conducted a cohort study based on a review of cases treated with monoclonal antibodies for severe asthma at our center. Data were extracted for demographics, eosinophil count, lung function (FEV1), exacerbation rate, and median dose of oral prednisone. Between-drug comparison was conducted by repeated measures ANOVA. The cohort included 62 patients receiving biological therapy. All biologic drugs were found to reduce exacerbation rate [F(1, 2) = 40.4, P < 0.0001] and prednisone use [F(1, 4) = 16, P < 0.001] significantly. ANOVA revealed no difference of efficacy endpoints between the different drugs. Eosinophil count was significantly reduced post-biologic treatment in the anti-interleukin-5 agents (P < 0.001) but not under treatment with omalizumab and dupilumab. All of the biological therapies were effective for improving clinical outcomes. None of the agents was clearly superior to any other. These data emphasize the need for severe asthma patients to be seen by pulmonary medicine specialists and offered, where appropriate, biological therapies.


Safe handovers for every patient: an interrupted time series analysis to test the effect of a structured discharge bundle in Dutch hospitals.
Patient handovers are often delayed, patients are hardly involved in their discharge process and hospital-wide standardised discharge procedures are lacking. The aim of this study was to implement a structured discharge bundle and to test the effect on timeliness of medical and nursing handovers, length of hospital stay (LOS) and unplanned readmissions. Interrupted time series with six preintervention and six postintervention data collection points (September 2015 to June 2017). Internal medicine and surgical wards PARTICIPANTS: Patients (≥18 years) admitted for more than 48 hours to surgical or internal medicine wards. The Transfer Intervention Procedure (TIP), containing four elements: planning the discharge date within 48 hours postadmission; arrangements for postdischarge care; preparing handovers and personalised patient discharge letter; and a discharge conversation 12-24 hours before discharge. The number of medical and nursing handovers sent within 24 hours. Secondary outcomes were median time between discharge and medical handovers, LOS and unplanned readmissions. Preintervention 1039 and postintervention 1052 patient records were reviewed. No significant change was observed in the number of medical and nursing handovers sent within 24 hours. The median (IQR) time between discharge and medical handovers decreased from 6.15 (0.96-15.96) to 4.08 (0.33-13.67) days, but no significant difference was found. No intervention effect was observed for LOS and readmission. In subgroup analyses, a reduction of 5.6 days in the median time between discharge and medical handovers was observed in hospitals with high protocol adherence and much attention for implementation. Implementation of a structured discharge bundle did not lead to improved timeliness of patient handovers. However, large interhospital variation was observed and an intervention effect on the median time between discharge and medical handovers was seen in hospitals with high protocol adherence. Future interventions should continue to create awareness of the importance of timely handovers. NTR5951; Results.


Efficacy of Tricaine (MS-222) and Hypothermia as Anesthetic Agents for Blocking Sensorimotor Responses in Larval Zebrafish.
Tricaine, or MS-222, is the most commonly used chemical anesthetic in zebrafish research. It is thought to act via blocking voltage-gated sodium channels, though its mechanism of action, particularly at the neuronal level, is not yet fully understood. Here, we first characterized the effects of tricaine on both body balance and touch responses in freely swimming animals, before determining its effect on the neural activity underlying the optokinetic response at the level of motion perception, sensorimotor signaling and the generation of behavior in immobilized animals. We found that the standard dose for larvae (168 mg/L) induced loss of righting reflex within 30 seconds, which then recovered within 3 minutes. Optokinetic behavior recovered within 15 minutes. Calcium imaging showed that tricaine interferes with optokinetic behavior by interruption of the signals between the pretectum and hindbrain. The motion sensitivity indices of identified sensory neurons were unchanged in larvae exposed to tricaine, though fewer such neurons were detected, leaving a small population of active sensory neurons. We then compared tricaine with gradual cooling, a potential non-chemical alternative method of anesthesia. While neuronal tuning appeared to be affected in a similar manner during gradual cooling, gradual cooling induced a surge in calcium levels in both the pretectum and hindbrain. This calcium surge, alongside a drop in heartrate, is potentially associated with harmful changes in physiology and suggests that tricaine is a better anesthetic agent than gradual cooling for zebrafish laboratory research.


Current management of juvenile dermatomyositis in Germany and Austria: an online survey of pediatric rheumatologists and pediatric neurologists.
Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease with broad variations of the individual course. Data on the optimal management are mostly lacking. Currently treatment decisions are often based on experts' opinions. In order to develop consensus-based treatment strategies for JDM in Germany a survey was pursued to analyze the current clinical practice. An online survey addressing all members of the Society for Pediatric Rheumatology (GKJR) in Germany and Austria and pediatric neurologists with expertise in JDM was performed in February/March of 2016. The questionnaire consisted of 5 case scenarios including diagnostic criteria, treatment of moderate, severe and refractory JDM, using either multiple choice or a 5-point Likert scale. Basic descriptive statistics were used to analyze the findings. The survey was completed by 60 pediatric rheumatologists and 7 pediatric neurologists experienced in the management of JDM. Typical findings allowing a diagnosis were considered to be: typical skin changes, proximal muscle weakness, MRI findings, elevated muscle enzymes, nailfold capillary changes, presence of calcinosis and muscle biopsy. Regarding induction treatment of moderate/severe JDM: 59%/74% opted for intermittent intravenous methylprednisolone (IVMP) pulse therapy, and 21%/40% for conventional high-dose oral glucocorticoids. Methotrexate (MTX) was the preferred disease-modifying conventional anti-rheumatic drug (cDMARD) for moderate and severe JDM. Regarding the management of refractory moderate or severe JDM, intravenous immune globulins, mycophenolate mofetil and rituximab were preferred treatment options. There is consensus about the diagnosis of JDM strongly supported by classic clinical and MRI findings. There is great variety in the treatment of JDM in Germany regarding both induction and maintenance therapy. The development of consensus-based treatment strategies for JDM based on harmonization of current clinical practice is essential in order to allow comparative effectiveness research in the future.


[Prescription of drugs in Norway to children aged 0-12 years].
The first part of a project initiated at the Department of Pharmacotherapeutics, University of Oslo, on use of drugs in the treatment of children involved a study of prescriptions in September 1986. All pharmacies in the country were asked to record all drugs prescribed to 0-12 year old children during one week. 87% of all Norwegian pharmacies took part in the study and data were recorded for 7,587 prescribed drugs. Drug prescribing was highest in the county of Hedmark, and lowest in the county of Troms. For the age group 0-10 years 23% more drugs were prescribed to boys than to girls. Infants (0-1 year) were prescribed drugs ten times more often than the oldest children. 3% of the infants (0-1 year) were prescribed drugs during the week the study took place. More than 43% of the total prescriptions were for drugs for the respiratory organs. Antasthmatics comprised the largest subgroup (796 prescribed drugs). Boys were prescribed 65% more antasthmatics than girls. Every 20th of the total prescriptions was for an oral decongestant. There are few rational reasons for prescribing drugs in this group. As a single group, systemic antibiotics were the drugs most often prescribed, and accounted for as much as 30% of the total prescriptions. The observed choice of antibiotics does not seem to agree with Norwegian recommendations.


Three-dimensional power Doppler vascular network assessment of adnexal masses: intraobserver and interobserver agreement analysis.
The purpose of this study was to assess intraobserver and interobserver agreement for tumor vascular network evaluation as assessed by 3-dimensional (3D) power Doppler sonography for discriminating benign from malignant adnexal masses. Stored 3D power Doppler angiographic volume data from 39 women with a diagnosis of a vascularized adnexal mass who were evaluated and treated at our institution were retrieved from our database for analysis. Two different examiners (observer A, with 6 years of experience in 3D sonography; and observer B, with 1 year of experience) reviewed 3D sonograms blinded to each other. Three-dimensional vascular network reconstruction was done with surface rendering in the color mode. Malignancy was considered in the presence of at least 2 of the following: irregular branching, vessel caliber changes, microaneurysms, and vascular lakes. A definitive histologic diagnosis was obtained in all cases. Intraobserver and interobserver agreement rates were estimated by calculating the kappa index. Twenty (51%) tumors were malignant, and 19 (49%) were benign. Intraobserver agreement was good for observer A (kappa = 0.69) and moderate for observer B (kappa = 0.54). Interobserver agreement was moderate (kappa = 0.49). We found intraobserver and interobserver agreement to be moderate for 3D power Doppler assessment of the vascular network in adnexal masses.


Reconstructing temporal and spatial dynamics from single-cell pseudotime using prior knowledge of real scale cell densities.
Modern cytometry methods allow collecting complex, multi-dimensional data sets from heterogeneous cell populations at single-cell resolution. While methods exist to describe the progression and order of cellular processes from snapshots of such populations, these descriptions are limited to arbitrary pseudotime scales. Here we describe MAPiT, an universal transformation method that recovers real-time dynamics of cellular processes from pseudotime scales by utilising knowledge of the distributions on the real scales. As use cases, we applied MAPiT to two prominent problems in the flow-cytometric analysis of heterogeneous cell populations: (1) recovering the kinetics of cell cycle progression in unsynchronised and thus unperturbed cell populations, and (2) recovering the spatial arrangement of cells within multi-cellular spheroids prior to spheroid dissociation for cytometric analysis. Since MAPiT provides a theoretic basis for the relation of pseudotime values to real temporal and spatial scales, it can be used broadly in the analysis of cellular processes with snapshot data from heterogeneous cell populations.


Fungal Diseases in Taiwan-National Insurance Data and Estimation.
The burden of fungal diseases based on the real-world national data is limited. This study aimed to estimate the Taiwan incident cases with selected fungal diseases in 2013 using the National Health Insurance Research Database (NHIRD) which covered 99.6% of the 23.4 million population. Over 80,000 incident cases were found and the majority were superficial infections including vulvovaginal candidiasis (477 per 100,000 adult women) and oral candidiasis (90 cases per 100,000 population). Common potentially life-threating fungal diseases were Pneumocystis pneumonia (5.35 cases per 100,000 population), candidemia (3.68), aspergillosis (2.43) and cryptococcal meningitis (1.04). Of the aforementioned cases cancer patients contributed 30.2%, 42.9%, 38.6% and 22.2%, respectively. Of 22,270 HIV-infected persons in NHIRD in 2013, four common diseases were Pneumocystis pneumonia (28.3 cases per 1000 HIV-infected patients), oral candidiasis (17.6), esophageal candidiasis (6.06) and cryptococcal meningitis (2.29). Of pulmonary aspergillosis 32.9% occurred in patients with chronic pulmonary diseases and 26.3% had a prior diagnosis of tuberculosis. There are some notable gaps related to insurance claim data. Cutaneous, urinary tract and eye fungal infections were not captured.


The Perception and Costs of the Interview Process for Plastic Surgery Residency Programs: Can the Process Be Streamlined?
The purpose of this study was to assess applicant perceptions and costs associated with the interview process for plastic surgery residency positions. This was a cross-sectional survey of applicants to the integrated- and independent-track residencies at the authors' institution. All applicants who were interviewed were invited to complete a Web-based survey on costs and perceptions of various components of the interview process. Descriptive and bivariate statistics were computed to compare applicants to the two program tracks. Fifty-three applicants were interviewed for residency positions; 48 completed a survey (90.5 percent response rate). Thirty-four applicants were candidates for the integrated program; 16 applicants were candidates for the independent program. The program spent $2763 per applicant interviewed; 63 percent of applicants spent more than $5000 on the interview process. More than 70 percent of applicants missed more than 7 days of work to attend interviews. Independent applicants felt less strongly that interviews were critical to the selection process and placed less value on physically visiting the hospital and direct, in-person interaction. Applicants placed little value on program informational talks. Applicants who had experience with virtual interviews felt more positively about the format of a video interview relative to those who did not. The residency interview process is resource intensive for programs and applicants. Removing informational talks may improve the process. Making physical tours and in-person interviews optional are other alternatives that merit future study.


Vasculogenic mimicry-potential target for glioblastoma therapy: an in vitro and in vivo study.
Glioblastoma is one of the most angiogenic human tumors and characterized by microvascular proliferations. A better understanding of glioblastoma vasculature is needed to optimize anti-angiogenic therapy that has shown a promising but incomplete efficacy. The present study examined 48 glioblastomas by CD34 endothelial marker periodic acid-Schiff (PAS) dual staining and found non-endothelial cell-lined blood vessels that were formed by tumor cells (vasculogenic mimicry, VM) existing in a fraction of these tumors. We hypothesized that CD133-positive glioblastoma stem-like cells (GSCs) may play a pivotal role in glioblastoma VM formation and then demonstrated in vitro and in vivo that a subset of GSCs were capable of vasculogenesis. Moreover, we found that several growth factors involved in normal angiogenesis were expressed in GSCs. We describe here a new mechanism of alternative glioblastoma vascularization and open a new perspective for the anti-vascular treatment strategy.


Centralized blood processing for the selenium and vitamin E cancer prevention trial: effects of delayed processing on carotenoids, tocopherols, insulin-like growth factor-I, insulin-like growth factor binding protein 3, steroid hormones, and lymphocyte viability.
This experiment examined the effects of delays in separation and freezing of whole blood components on analytes of interest in studies of prostate cancer prevention, in order to evaluate the feasibility of centralized processing of blood for the multisite Selenium and Vitamin E Cancer Prevention Trial. Blood from 40 healthy men was subjected to four treatment protocols, allowing the contrast of immediate processing to delays of 32, 72, and 144 hours. At 32 hours, simulating refrigerated storage and overnight shipping, there was a 2.9% decrease (95% confidence interval, 0.7-5.1) in insulin-like growth factor-I (IGF-I) but no significant change in carotenoids, tocopherols, testosterone, 3alpha-androstanediol glucuronide (AAG), sex hormone-binding globulin (SHBG) or insulin-like growth factor binding protein 3 (IGFBP3). A 144-hour processing delay, simulating weekend blood collection or shipping delay, resulted in significant changes in gamma-tocopherol (-1.5%), IGF-I (-5.7%), IGFBP3 (-2.9%), SHBG (-4.0%), testosterone (+4.7%), and AAG (+5.5%). The rank-order and intraclass correlations between analytes from blood processed immediately and those subjected to delayed processing were 0.96 or higher for carotenoids, tocopherols, AAG, and SHBG, and between 0.87 and 0.95 for IGF-I, IGFBP3, and testosterone. A 32-hour delay decreased lymphocyte viability from 82.5% to 75.0% (P = 0.45), but a 72-hour delay decreased viability to 36.8% (P < 0.001). Overnight shipping and centralized processing is an acceptable approach to blood collection in large multisite trials examining the cancer-related measures proposed in the Selenium and Vitamin E Cancer Prevention Trial. Longer processing delays, however, have small but statistically significant effects on many analytes and substantially decrease lymphocyte viability.


Zebrafish kit mutation reveals primary and secondary regulation of melanocyte development during fin stripe regeneration.
Fin regeneration in adult zebrafish is accompanied by re-establishment of the pigment stripes. To understand the mechanisms underlying fin stripe regeneration and regulation of normal melanocyte stripe morphology, we investigated the origins of melanocytes in the regenerating fin and their requirement for the kit receptor tyrosine kinase. Using pre-existing melanin as a lineage tracer, we show that most fin regeneration melanocytes develop from undifferentiated precursors, rather than from differentiated melanocytes. Mutational analysis reveals two distinct classes of regeneration melanocytes. First, an early regeneration class develops dependent on kit function. In the absence of kit function and kit-dependent melanocytes, a second class of melanocytes develops at later stages of regeneration. This late kit-independent class of regeneration melanocytes has little or no role in wild-type fin stripe development, thus revealing a secondary mode for regulation of fin stripes. Expression of melanocyte markers in regenerating kit mutant fins suggests that kit normally acts after mitf and before dct to promote development of the primary kit-dependent melanocytes. kit-dependent and kit-independent melanocytes are also present during fin stripe ontogeny in patterns similar to those observed during regeneration.


Inter-annual and inter-species tree growth explained by phenology of xylogenesis.
Wood formation determines major long-term carbon (C) accumulation in trees and therefore provides a crucial ecosystem service in mitigating climate change. Nevertheless, we lack understanding of how species with contrasting wood anatomical types differ with respect to phenology and environmental controls on wood formation. In this study, we investigated the seasonality and rates of radial growth and their relationships with climatic factors, and the seasonal variations of stem nonstructural carbohydrates (NSC) in three species with contrasting wood anatomical types (red oak: ring-porous; red maple: diffuse-porous; white pine: coniferous) in a temperate mixed forest during 2017-2019. We found that the high ring width variability observed in both red oak and red maple was caused more by changes in growth duration than growth rate. Seasonal radial growth patterns did not vary following transient environmental factors for all three species. Both angiosperm species showed higher concentrations and lower inter-annual fluctuations of NSC than the coniferous species. Inter-annual variability of ring width varied by species with contrasting wood anatomical types. Due to the high dependence of annual ring width on growth duration, our study highlights the critical importance of xylem formation phenology for understanding and modelling the dynamics of wood formation.


The MyoD family of myogenic factors is regulated by electrical activity: isolation and characterization of a mouse Myf-5 cDNA.
A full-length cDNA coding for a homolog of the human Myf-5 was isolated from a BC3H-1 mouse library and characterized. The clone codes for a protein of 255 amino acids that is 89%, 88% and 68% identical to the human, bovine and Xenopus myf-5, respectively. The mouse Myf-5 cDNA (mmyf-5), as well as sequences coding for MyoD, myogenin and Mrf-4, were used to probe Northern blots to analyze the effects of innervation on the expression of the MyoD family of myogenic factors. Mouse myf-5, MyoD and myogenin mRNAs levels were found to decline in hind limb muscles of mice between embryonic day 15 (E15) and the first postnatal week, a period that coincides with innervation. In contrast, Mrf-4 transcripts increase during this period and reach steady-state levels by 1-week after birth. To distinguish if the changes in myogenic factor expression are due to a developmental program or to innervation, mRNA levels were analyzed at different times after muscle denervation. Mmyf-5 transcripts begin to accumulate 2 days postdenervation; after 1 week levels are 7-fold higher than in innervated muscle. Mrf-4, MyoD and myogenin transcripts begin to accumulate as soon as 8h after denervation, and attain levels that are 8-, 15- and 40-fold higher than found in innervated skeletal muscle, respectively. The accumulation of these three mRNAs precedes the increase of nicotinic acetylcholine receptor alpha subunit transcripts, a gene that is transcriptionally regulated by MyoD-related factors in vitro. Using extracellular electrodes to directly stimulate in situ the soleus muscle of rats, we found that 'electrical activity' per se, in absence of the nerve, represses the increases of myogenic factor mRNAs associated with denervation.


Management of hyperglycemia during the perioperative period.
Hyperglycemia is frequently encountered in the inpatient setting and is distinctly associated with poor clinical outcomes. Recent literature suggests an association between stringent glycemic control and increased mortality, thus keeping optimal glycemic targets a relevant subject of debate. In the surgical population, hyperglycemia with or without diabetes mellitus may be unrecognized. Factors contributing to hyperglycemia in the hospital include critical illness, use of certain drugs, use of enteral or parenteral nutrition, and variability in oral or nutritional intake as can occur when patients are prepared for procedures or surgery. A sensible approach to managing hyperglycemia in this population includes preoperative recognition of diabetes mellitus and risks for inpatient hyperglycemia. Judicious control of glycemia during the pre-, intra-, and postoperative time periods with avoidance of hypoglycemia mandates the need for a strategy for patient management that extend to time of discharge. We review the consequences of uncontrolled perioperative hyperglycemia, discuss current clinical guidelines and recent controversies, and provide practical tools for glycemic control in the surgical population.


[Department of Molecular Immunology--25 years].
Department of Molecular Immunology of Palladin Institute of Biochemistry was founded 25 years ago as the Laboratory of Immunochemistry uniting, at the beginning, a small group of scientists. In 1982 the Laboratory was transformed into the Department of Molecular Immunology. The first research was made on studding the biological effect and the mechanisms of action of phosphonates and bisphosphonates--phosphororganic analogues of inorganic pyrophosphate or closely related in structure molecules having P-C bond instead of P-O bond. As a result the immuno-modulatory activity of methylene-bis-phosphonic acid was discovered and a set of immuno-vector, immuno-toxin and anti-tumour constructs were designed. The researchers of the Department were the first in the USSR who started the biochemistry of activated lymphocytes, immunochemical analysis of peptides and proteins, implemented immunoenzyme methods and cytofluorimetry to study immunocompetent cells. In particular, monoclonal and polyclonal antibodies were obtained and used to study the antigenic structure of neurotoxin apamin, cytochrome c, neurospecific proteins S-100 and 14-3-2, nicotinic acetylcholine receptors, pertusis and diphtheria toxins, different antigens of Mycobacterium bovis and of fibrin(ogen) and its fragments and others. The new site of fibrin polymerization was localized. The novel information about the nature of polyreactive immunoglobulins and their influence on the development of the humoral immune response was obtained. A range of reagents for immunodiagnostic tests were developed as the outcome of this research work. The negative effect of small doses of radiation on natural immunity in people working during the cleaning of Chernobyl nuclear plant was first demonstrated by the researchers of the Department in co-operation with their colleagues from a couple of Kiev immunology laboratories. In particular the suppression of NK cells function and structure was shown.


A review of autobiographical memory studies on patients with schizophrenia spectrum disorders.
Patients suffering from schizophrenia spectrum disorders demonstrate various cognitive deficiencies, the most pertinent one being impairment in autobiographical memory. This paper reviews quantitative research investigating deficits in the content, and characteristics, of autobiographical memories in individuals with schizophrenia. It also examines if the method used to activate autobiographical memories influenced the results and which theoretical accounts were proposed to explain the defective recall of autobiographical memories in patients with schizophrenia. PsycINFO, Web of Science, and PubMed databases were searched for articles published between January 1998 and December 2018. Fifty-seven studies met the inclusion criteria. All studies implemented the generative retrieval strategy by inducing memories through cue words or pictures, the life-stage method, or open-ended retrieval method. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines were followed for this review. Most studies reported that patients with schizophrenia retrieve less specific autobiographical memories when compared to a healthy control group, while only three studies indicated that both groups performed similarly on memory specificity. Patients with schizophrenia also exhibited earlier reminiscence bumps than those for healthy controls. The relationship between comorbid depression and autobiographical memory specificity appeared to be independent because patients' memory specificity improved through intervention, but their level of depression remained unchanged. The U-shaped retrieval pattern for memory specificity was not consistent. Both the connection between the history of attempted suicide and autobiographical memory specificity, and the relationship between psychotic symptoms and autobiographical memory specificity, remain inconclusive. Patients' memory specificity and coherence improved through cognitive training. The overgeneral recall of autobiographical memory by patients with schizophrenia could be attributed to working memory, the disturbing concept of self, and the cuing method implemented. The earlier reminiscence bump for patients with schizophrenia may be explained by the premature closure of the identity formation process due to the emergence of psychotic symptoms during early adulthood. Protocol developed for this review was registered in PROSPERO (registration no: CRD42017062643).


A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira®) in the treatment of active rheumatoid arthritis.
This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10-25 mg/week). We report results for the first 26 weeks of treatment. Patients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (-12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28-4(CRP)], European League Against Rheumatism (EULAR) response, DAS28-4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26. Patients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28-4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was -2.98% and corresponding CIs-95% CI (-10.38%, 4.44%) and 90% CI (-9.25%, 3.28%)-were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU). The study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX. ClinicalTrials.gov Identifier: NCT02480153 . First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29 . Start date: October 27, 2014.


[Experimental study of morphology and electrophysiology on denervated skeletal muscle].
In order to provide the scientific basis to find out a practical and effective method to evaluate the degree of muscle atrophy and a better method of prevention and treatment of skeletal muscle atrophy. Forty-two adult Spray-Dawley rats were used and the model of denervated gastrocnemius muscle was established by cutting off the tibial nerve. The muscle wet weight, diameter and cross section area of myocyte were measured. The motor end-plate, fibrillation potential amplitude and frequency of denervated skeletal muscle were observed. The muscle wet weight rapidly reduced within 4 weeks. Afterwards, it maintained about 30 per cent of normal value, and the diameter and cross section area of myocyte progressively reduced. The motor end-plate slightly changed within 4 weeks, but its degeneration accelerated in 6 weeks and disappeared after 16 weeks. The fibrillation potential amplitude was maximum at 2 weeks and it progressively reduced after 12 weeks of muscle denervation. The changes of amplitude and frequency were consistent with the degeneration of end-plate. The muscle wet weight, diameter and cross section area of myocyte, fibrillation potential amplitude and frequency could be considered as the morphological and electrophysiological indexes of muscle atrophy degree. It's suggested that the repairing operation of peripheral nerve should be performed before the disappearance of motor end-plate.


Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner.
Maintaining the cholesterol homeostasis is essential for normal CNS functioning. The enzyme responsible for elimination of cholesterol excess from the brain is cholesterol 24-hydroxylase (Cyp46). Since cholesterol homeostasis is disrupted following brain injury, in this study we examined the effect of right sensorimotor cortex suction ablation on cellular and temporal pattern of Cyp46 expression in the rat brain. Increased expression of Cyp46 at the lesion site at all post injury time points (2, 7, 14, 28 and 45 days post injury, dpi) was detected. Double immunofluorescence staining revealed colocalization of Cyp46 expression with different types of glial cells in time-dependent manner. In ED1(+) microglia/macrophages Cyp46 expression was most prominent at 2 and 7 dpi, whereas Cyp46 immunoreactivity persisted in reactive astrocytes throughout all time points post-injury. However, during the first 2 weeks Cyp46 expression was enhanced in both GFAP(+) and Vim(+) astrocytes, while at 28 and 45 dpi its expression was mostly associated with GFAP(+) cells. Pattern of neuronal Cyp46 expression remained unchanged after the lesion, i.e. Cyp46 immunostaining was detected in dendrites and cell body, but not in axons. The results of this study clearly demonstrate that in pathological conditions, like brain injury, Cyp46 displayed atypical expression, being expressed not only in neuronal cells, but also in microglia and astrocytes. Therefore, injury-induced expression of Cyp46 in microglial and astroglial cells may be involved in the post-injury removal of damaged cell membranes contributing to re-establishment of the brain cholesterol homeostasis.


Palladium(ii) and palladium(ii)-silver(i) complexes with N-heterocyclic carbene and zwitterionic thiolate mixed ligands: synthesis, structural characterization and catalytic properties.
The integration of a geometrically rigid Pd(ii), a coordinatively monotonous N-heterocyclic carbene 1,3-dimethylimidazoline-2-ylidene (IMe), and a flexible zwitterionic thiolate 4-(trimethylammonio)benzenethiolate (Tab) affords a class of Pd-IMe-Tab complexes with various nuclearities, namely, trans-[Pd(IMe)2(Tab)2](OTf)2 (2, mononuclear), cis-[Pd(IMe)2(Tab)2](OTf)(Cl) (3a, mononuclear), cis-[Pd(IMe)2(Tab)2](PF6)2·MeCN (3b·MeCN, mononuclear), [Pd2(IMe)4(Tab)2](PF6)4·2MeCN (4·2MeCN, dinuclear) and [Pd4(IMe)4(Tab)6](OTf)6(Cl)2 (5, tetranuclear). Further presence of Ag(i) in the assembly provides a heterometallic octanuclear cluster of [Pd4Ag4(IMe)8(Tab)10](PF6)12 (6). Compounds 2-6 are formed by the reaction of trans-Pd(IMe)2Cl2 (1) with various additional reagents via different reaction pathways. These compounds are characterized by means of FT-IR, 1H and 13C NMR, ESI-MS, elemental analysis and X-ray crystallography. Notably, the skeleton of compound 5 features a [Pd4S4] parallelogram wherein each of the four Pd(ii) centers bisects the edge defined by the S atoms. The main skeleton of compound 6 is an oval-shaped Pd4Ag4S10 unit, featuring an edge-fused norbornane-like (Pd2Ag4S6) framework appended by two additional PdS2 motifs at the polar positions. Compounds 5 and 6 also feature PdPd (5), PdAg and AgAg (6) interactions. Compound 5 as a representative example is highly effective at catalyzing Suzuki-Miyaura couplings in water, highlighting the potential of applying these types of homo- and heterometallic clusters as catalysts for organic transformations in environmentally benign media.


Reperfusion injury of the liver: role of mitochondria and protection by glutathione ester.
Reperfusion injury of the liver is characterized by intravascular oxidative stress and GSH consumption. Whether mitochondria contribute to hepatocellular damage has never been elucidated. Therefore, we assessed mitochondrial function and redox state during reperfusion and the effect of glutathione monoethyl ester (GSHE) administration, which may replenish the GSH pool. Rats were subjected to partial hepatic ischemia (90 min) followed by reperfusion. Mitochondrial function was assessed in vivo and in vitro by the KICA breath test and the ATP synthase activity. Just prior to the start of reperfusion, rats received 5 mmol/kg of GSHE or saline iv. ALT, total and oxidized (GSSG) glutathione, GSHE, and CYS were measured in plasma and liver. GSH, GSSG, malondialdehyde (MDA), and carbonyl proteins were measured in mitochondria. The extent of necrosis was also estimated. Sham-operated rats served as controls. Reperfusion markedly increased ALT (>1500 U/L) and doubled the liver content of MDA and carbonyl proteins. Mitochondrial GSH decreased approximately 30%, without increase of GSSG. The in vivo KICA breath test was not significantly impaired by reperfusion. In contrast, both KICA decarboxylation and ATP synthase activity were both reduced by approximately 50% in mitochondria isolated from reperfused livers. GSHE administration significantly decreased ALT ( approximately 40%), protected ATP synthase activity, and reduced the extent of necrosis. Compared to controls, plasma GSHE and plasma GSH at 1 h were lower in rats subjected to ischemia. GSHE was higher in reperfused lobes than in continuously perfused ones and the concentration of GSH was significantly higher in ischemic liver than in untreated animals, indicating that the uptake of GSHE is increased in postischemic liver. GSHE prevented the reperfusion-associated increase of oxidized products in liver and mitochondria. Reperfusion of ischemic liver is associated with oxidative modifications and functional impairment of mitochondria. GSHE protects against reperfusion injury, possibly by providing intra- and extracellular GSH.


[Invasive emergency techniques--decompression of the pleura].
On-scene invasive emergency procedures, such as cricothyroidotomy, chest drain, intraosseous puncture or even on-field-amputation, are often unavoidable, when indicated, and present a major challenge for the emergency physician. Personal, temporal or local conditions are often unsuitable. Even with regular intervention by the emergency medical service, "last resort" measures occur very infrequently, particularly in relation to paediatric emergencies. Beside a theoretical education, practice-oriented course concepts are necessary to achieve a high quality of these measures. This article presents the use of decompression of the pleura on adults and children, with reference to indication, implementation, problems and risks. It is the second part of a series of four articles on the subject of invasive emergency techniques.


Guided bone regeneration of non-contained mandibular buccal bone defects using deproteinized bovine bone mineral and a collagen membrane: an experimental in vivo investigation.
The aim of this pre-clinical in vivo study was to analyse different stages of wound healing after guided bone regeneration in non-contained mandibular buccal bone defects. Eighteen female beagle dogs, between 1.5 and 2 years old, were used. Buccal bone defects were created in the mandible following extraction of the mesial roots of M1, P4, the distal root of P3 and booth roots of P2. Augmentation procedures of the healed defects were performed 3 months later using a bone replacement graft (T1), an absorbable collagen membrane (T2) or a combination of both procedures (T3). Using a randomized block study design, four stages of healing in two groups of dogs were examined (4 days, 2, 6 weeks and 3 months). The animals were euthanized, and biopsies obtained at the end of each of the study periods were prepared for histological examination. The different reconstructive procedures resulted in regenerated tissue compartments of varying size that contained newly formed bone, non-mineralized tissue and bone augmentation biomaterial when a bone replacement graft was used. While the proportions of mineralized tissue increased and non-mineralized tissue decreased over time in the three groups, the changes in proportions of the DBBM material were small. Initial defect depth, healing time and treatment group significantly influenced the percentage of mineralized tissue obtained. The multivariate multilevel analysis showed that significantly larger area proportions of mineralized tissue were obtained when the T2 sites were compared with T1 and T3 sites, what highlights the importance of the barrier membrane effect for attaining new bone formation. Only in the larger size defects (M1) total ROI at T3 and T1 sites was significantly larger than at T2, what highlights the importance of using a bone replacement graft as a space maintenance scaffold. It is suggested that healing following augmentation of non-contained buccal bone defects was characterized by a gradual shift in the relative proportions of non-mineralized and mineralized tissue components.


Dual roles for DNA polymerase theta in alternative end-joining repair of double-strand breaks in Drosophila.
DNA double-strand breaks are repaired by multiple mechanisms that are roughly grouped into the categories of homology-directed repair and non-homologous end joining. End-joining repair can be further classified as either classical non-homologous end joining, which requires DNA ligase 4, or "alternative" end joining, which does not. Alternative end joining has been associated with genomic deletions and translocations, but its molecular mechanism(s) are largely uncharacterized. Here, we report that Drosophila melanogaster DNA polymerase theta (pol theta), encoded by the mus308 gene and previously implicated in DNA interstrand crosslink repair, plays a crucial role in DNA ligase 4-independent alternative end joining. In the absence of pol theta, end joining is impaired and residual repair often creates large deletions flanking the break site. Analysis of break repair junctions from flies with mus308 separation-of-function alleles suggests that pol theta promotes the use of long microhomologies during alternative end joining and increases the likelihood of complex insertion events. Our results establish pol theta as a key protein in alternative end joining in Drosophila and suggest a potential mechanistic link between alternative end joining and interstrand crosslink repair.


Interaction of Nucleotides with a Trinuclear Terbium(III)-Dizinc(II) Complex: Efficient Sensitization of Terbium Luminescence by Guanosine Monophosphate and Application to Real-Time Monitoring of Phosphodiesterase Activity.
An in-depth study of the interaction of a trinuclear terbium(III)-dizinc(II) complex with an array of nucleotides differing in the type of nucleobase and number of phosphate groups, as well as cyclic versus acyclic variants, is presented. The study examined the nature of the interaction and the efficiency at which guanine was able to sensitize terbium(III) luminescence. Competitive binding and titration studies were performed to help establish the nature/mode of the interactions. These established that (1) interaction occurs by the coordination of phosphate groups to zinc(II) (in addition to uridine in the case of uridine monophosphate), (2) acyclic nucleotides bind more strongly than cyclic counterparts because of their higher negative charge, (3) guanine-containing nucleotides are able to sensitize terbium(III) luminescence with the efficiency of sensitization following the order guanosine monophosphate (GMP) > guanosine diphosphate > guanosine triphosphate because of the mode of binding, and (4) nucleoside monophosphates bind to a single zinc(II) ion, whereas di- and triphosphates appear to bind in a bridging mode between two host molecules. Furthermore, it has been shown that guanine is a sensitizer of terbium(III) luminescence. On the basis of the ability of GMP to effectively sensitize terbium(III)-based luminescence while cyclic GMP (cGMP) does not, the complex has been utilized to monitor the catalytic conversion of cGMP to GMP by a phosphodiesterase enzyme in real time using time-gated luminescence on a benchtop fluorimeter. The complex has the potential to find broad application in monitoring the activity of enzymes that process nucleotides (co)substrates, including high-throughput drug-screening programs.


Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects.
This study was designed to compare central serotonergic function in depressed patients and healthy comparison subjects by examining neuroendocrine and mood responses to intravenous L-tryptophan. One hundred twenty-six drug-free patients with DSM-III-R major depression (109 unipolar, 17 bipolar; 68 melancholic, 58 nonmelancholic; 28 psychotic, and 98 nonpsychotic patients) and 58 healthy comparison subjects participated. After an overnight fast, subjects received an intravenous infusion of L-tryptophan, 7 g. Blood was obtained for determination of serum prolactin, serum growth hormone (GH), and plasma tryptophan levels. Visual analogue scales were used to assess mood. Prolactin responses were blunted in nonmelancholic and higher in melancholic and psychotic depressed patients, while GH responses were blunted in combined unipolar, nonmelancholic, and nonpsychotic depressed patients. Controlling for baseline biological, clinical, and demographic factors eliminated the higher prolactin response in the melancholic and psychotic patients, attenuated the blunted GH response in the unipolar patients, and revealed a blunted GH response in the melancholic patients. Patients and comparison subjects differed on five of 13 mood responses, primarily because of baseline differences. These findings are consistent with previous studies demonstrating blunted neuroendocrine responses to intravenous L-tryptophan in depression. Restriction of these findings to specific subtypes of depression may reflect a differential role of serotonergic abnormalities in these subtypes.


Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1.
The functional role of nuclear factor of activated T-cells (NFAT), a key regulator of the immune response, in bladder cancer progression remains uncertain. In this study, we assessed biological significance of NFAT in human bladder cancer. Immunohistochemistry detected nuclear/cytoplasmic NFATc1 signals in 14 (21.5%)/34 (52.3%), respectively, of 65 muscle-invasive bladder carcinomas and showed that patients with nuclear NFATc1-positive tumor had a significantly higher risk of disease progression (P = 0.006). In bladder cancer cell lines, cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressant drugs/non-selective NFAT inhibitors, attenuated NFATc1 expression and its nuclear translocation, NFAT transcriptional activity, and the expression of cyclooxygenase-2 and c-myc, downstream targets of NFATc1. NFAT inhibition via NFATc1-small interfering RNA (siRNA) or treatment with these NFAT inhibitors resulted in decreases in cell viability/colony formation, cell migration/invasion, and the expression/activity of MMP-2 and MMP-9, as well as an increase in apoptosis, in the parental/control lines. No significant additional inhibition in the viability and invasion of NFATc1-siRNA cells was seen. In xenograft-bearing mice, CsA and FK506 significantly retarded tumor growth. These results suggest that NFATc1 plays an important role in bladder cancer outgrowth. Thus, NFATc1 inactivation, especially using CsA and FK506, has the potential of being a therapeutic approach for bladder cancer.


Magnitude and location of surface charges on Myxicola giant axons.
The effects of changes in the concentration of calcium in solutions bathing Myxicola giant axons on the voltage dependence of sodium and potassium conductance and on the instantaneous sodium and potassium current-voltage relations have been measured. The sodium conductance-voltage relation is shifted along the voltage axis by 13 mV in the hyperpolarizing direction for a fourfold decrease in calcium concentration. The potassium conductance-voltage relation is shifted only half as much as that for sodium. There is no effect on the shape of the sodium and potassium instantaneous current-voltage curves: the normal constant-field rectification of potassium currents is maintained and the normal linear relationship of sodium currents is maintained. Considering that shifts in conductances would reflect the presence of surface charges near the gating machinery and that shape changes of instantaneous current-voltage curves would reflect the presence of surface charges near the ionic pores, these results indicate a negative surface charge density of about 1 electronic charge per 120 A2 near the sodium gating machinery, about 1 e/300 A2 for the potassium gating machinery, and much less surface charge near the sodium or potassium pores. There may be some specific binding of calcium to these surface charges with an upper limit on the binding constant of about 0.2 M-1. The differences in surface charge density suggest a spatial separation for these four membrane components.


Capturing basic movements for mobile platforms embedded with motion sensors.
A novel experimental setup using accelerometer and gyroscope sensors embedded on a single board along with a distance-based pattern recognition algorithm is presented for accurately identifying basic movements for possible application in gaming using a mobile platform. As an example, we considered some basic step sequences in the popular dance game (e.g., dance dance revolution), and could detect these movements with a reasonably high probability. We envision that the experimental results presented in this paper will motivate future research in the world of mobile gaming applications using advanced smart phones with a dual module design.


In vitro inhibition of human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effects on inhibitory potential.
1. Rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is being developed for the treatment of cutaneous melanoma and hepatocellular carcinoma. Interestingly, rose bengal can generate singlet oxygen species upon exposure to light. 2. We evaluated rose bengal as an in vitro inhibitor of cytochrome P450 (CYP) or UDP-glucuronosyltransferase (UGT) enzymes in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHHs) under both yellow light and dark conditions. 3. Rose bengal directly inhibited CYP3A4/5 and UGT1A6 in HLM under yellow light with inhibitor concentration that causes 50% inhibition (IC50) values of 0.072 and 0.035 μM, respectively; whereas much less inhibition was observed in the dark with the IC50 values increasing 43- and 120-fold, respectively. To determine if a more physiologically-relevant test system could be protected from such an effect, rose bengal was evaluated as an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5 and UGT enzymes in CHH. All IC50 values were similar (64 ± 8 μM) and little to no effect of light on inhibitory potential was observed. 4. Given the IC50 values in CHH increased an order of magnitude compared to HLM and the atypical pharmacokinetics of the drug, the risk of rose bengal to cause clinically relevant drug-drug interactions is likely low, particularly when administered to cancer patients on an intermittent schedule.


Role of UTX in retinoic acid receptor-mediated gene regulation in leukemia.
Human UTX, a member of the Jumonji C family of proteins, associates with mixed-lineage leukemia 3/4 complexes. Stimulation with retinoic acid leads to the recruitment of UTX-containing complexes to HOX genes, which results in demethylation of histone H3 lysine 27 and concomitant methylation of histone H3 lysine 4. Here, we show that UTX interacts with the retinoic acid receptor α (RARα) and that this interaction is essential for proper differentiation of leukemic U937 cells in response to retinoic acid. UTX occupies the promoters of several RAR target genes and regulates their transcriptional output by modulating ASH2L complex recruitment. Overexpression of UTX in promyelocytic NB4 cells results in enhanced cellular differentiation upon retinoic acid treatment. Our results show that UTX is important for RAR-mediated transcription and provide insight into the critical role of cross talk between histone H3 lysine 4 methylation and histone H3 lysine 27 demethylation during cellular differentiation.


The challenge of clinical end points in sickle cell disease.
As most patients with sickle cell disease (SCD) do not have access to curative therapies, the availability of drug therapies that can modify disease severity remains highly desirable. Despite an increased understanding of the pathophysiology of SCD, only 4 drugs are approved by the US Food and Drugs Administration. Most drug trials in SCD have involved the use of acute pain episodes as the primary clinical end point. These studies have typically been to prevent or shorten the duration of such episodes. To date, no drug has received regulatory approval for shortening the duration of acute vaso-occlusive complications, likely highlighting the complex pathophysiology of acute pain episodes. Trials to prevent acute pain episodes have largely evaluated those episodes requiring health care use as a surrogate end point. However, with differences in culture and health care practices among countries, health care use may not reliably predict clinically important effects on acute pain episodes. This article discusses issues related to the use of health care use as the primary end point for prevention trials of acute pain episodes and highlights the importance of evaluating patient-reported outcomes as well as other SCD-related complications as outcome measures.


Prompt-Based Tuning of Transformer Models for Multi-Center Medical Image Segmentation of Head and Neck Cancer.
Medical image segmentation is a vital healthcare endeavor requiring precise and efficient models for appropriate diagnosis and treatment. Vision transformer (ViT)-based segmentation models have shown great performance in accomplishing this task. However, to build a powerful backbone, the self-attention block of ViT requires large-scale pre-training data. The present method of modifying pre-trained models entails updating all or some of the backbone parameters. This paper proposes a novel fine-tuning strategy for adapting a pretrained transformer-based segmentation model on data from a new medical center. This method introduces a small number of learnable parameters, termed prompts, into the input space (less than 1% of model parameters) while keeping the rest of the model parameters frozen. Extensive studies employing data from new unseen medical centers show that the prompt-based fine-tuning of medical segmentation models provides excellent performance regarding the new-center data with a negligible drop regarding the old centers. Additionally, our strategy delivers great accuracy with minimum re-training on new-center data, significantly decreasing the computational and time costs of fine-tuning pre-trained models. Our source code will be made publicly available.


[Theoretical model of the B-Z transition in DNA with an arbitrary sequence].
A statistical-mechanical model is suggested that makes it possible to describe the B-Z transition in DNA with an arbitrary sequence of nucleotides. The key point consists in allowance for the fact that each base pair can assume one of the two states with different energies. One of these states corresponds to the standard Z-form with purines in the syn conformation and pyrimidines in the anti conformation. However, in natural DNA sequences such standard base-pair conformations should be interrupted by energetically unfavorable conformations (syn for pyrimidines and anti for purines). Open regions and cruciform structures are also allowed for in the model. The probabilities of formation of the Z-form stretches, open regions and cruciform structures have been calculated for different values of parameters for pBR322 and pAO3 DNA.


Multiple sclerosis and exposure to organic solvents, investigated by genetic polymorphisms of the GSTM1 and CYP2D6 enzyme systems.
An association between multiple sclerosis (MS) and exposure to organic solvents has been discussed. Organic solvents are metabolised by enzyme systems like glutathione Stransferase M1 (GSTM1) and CYP2D6, which express polymorphisms in the general population. GSTM1 null genotype has been associated with solvent-induced chronic toxic encephalopathy. Our aim was to see if a defect in one of these enzyme systems could explain the association between MS and exposure to organic solvents. In our study, 50 patients with MS were investigated, including 24 who had been significantly exposed to organic solvents and 26 who were not exposed. Polymerase chain reaction-based methods were used for genotyping GSTM1 and CYP2D6 polymorphisms in leukocyte DNA. No differences in genetic predisposition were found between MS patients exposed and those not exposed to organic solvents regarding GSTM1 null or CYP2D6 poor metaboliser genotypes. The possible association between multiple sclerosis and solvents may not, as for chronic toxic encephalopathy, be explained by defects in these systems.


Fiber-orientation independent component of R2* obtained from single-orientation MRI measurements in simulations and a post-mortem human optic chiasm.
The effective transverse relaxation rate (R2*) is sensitive to the microstructure of the human brain like the g-ratio which characterises the relative myelination of axons. However, the fibre-orientation dependence of R2* degrades its reproducibility and any microstructural derivative measure. To estimate its orientation-independent part (R2,iso*) from single multi-echo gradient-recalled-echo (meGRE) measurements at arbitrary orientations, a second-order polynomial in time model (hereafter M2) can be used. Its linear time-dependent parameter, β1, can be biophysically related to R2,iso* when neglecting the myelin water (MW) signal in the hollow cylinder fibre model (HCFM). Here, we examined the performance of M2 using experimental and simulated data with variable g-ratio and fibre dispersion. We found that the fitted β1 can estimate R2,iso* using meGRE with long maximum-echo time (TEmax ≈ 54 ms), but not accurately captures its microscopic dependence on the g-ratio (error 84%). We proposed a new heuristic expression for β1 that reduced the error to 12% for ex vivo compartmental R2 values. Using the new expression, we could estimate an MW fraction of 0.14 for fibres with negligible dispersion in a fixed human optic chiasm for the ex vivo compartmental R2 values but not for the in vivo values. M2 and the HCFM-based simulations failed to explain the measured R2*-orientation-dependence around the magic angle for a typical in vivo meGRE protocol (with TEmax ≈ 18 ms). In conclusion, further validation and the development of movement-robust in vivo meGRE protocols with TEmax ≈ 54 ms are required before M2 can be used to estimate R2,iso* in subjects.


The Shwachman-Bodian-Diamond syndrome associated protein interacts with HsNip7 and its down-regulation affects gene expression at the transcriptional and translational levels.
The Shwachman-Bodian-Diamond syndrome (SDS) is an autosomal disorder with pleiotropic phenotypes including pancreatic, skeletal and bone marrow deficiencies and predisposition to hematological dysfunctions. SDS has been associated to mutations in the SBDS gene, encoding a highly conserved protein that was shown to function in ribosome biogenesis in yeast. In this work, we show that SBDS is found in complexes containing the human Nip7 ortholog. Analysis of pre-rRNA processing in a stable SBDS knock-down HEK293-derivative cell line revealed accumulation of a small RNA which is a further indication of SBDS involvement in rRNA biosynthesis. Global transcription and polysome-bound mRNA profiling revealed that SBDS knock-down affects expression of critical genes involved in brain development and function, bone morphogenesis, blood cell proliferation and differentiation, and cell adhesion. Expression of a group of growth and signal transduction factors and of DNA damage response genes is also affected. In SBDS knock-down cells, 34 mRNAs showed decreased and 55 mRNAs showed increased association to polysomes, among which is a group encoding proteins involved in alternative splicing and RNA modification. These results indicate that SBDS is required for accurate expression of genes important for proper brain, skeletal, and blood cell development.


Dengzhanxixin Injection Ameliorates Cognitive Impairment Through a Neuroprotective Mechanism Based on Mitochondrial Preservation in Patients With Acute Ischemic Stroke.
Acute ischemic stroke (AIS) is a global health burden and cognitive impairment is one of its most serious complication. Adequate interventions for AIS may have the potential to improve cognitive outcomes. In the present study, we selected Erigeron breviscapus (Vaniot) Hand.-Mazz. injection (Dengzhanxixin injection, DZXI), a widely used Chinese herbal injection, in contrast to edaravone as the positive control drug to test its potential to ameliorates neurological and cognitive impairments caused by AIS. We performed a 2-week randomized trial with these two drugs in AIS patients presenting mild to moderate cognitive impairments. Neuropsychological tests and MRI examinations showed that DZXI attenuated the neurological and cognitive impairments of patients and protected the grey matter in specific regions from ischemic damage. Notably, DZXI exerted better effects than edaravone in some neuropsychological tests, probably due to the protective effect of DZXI on grey matter. To explore the therapeutic mechanisms, we carried out an experiment with a middle cerebral artery occlusion rat model. We found that DZXI decreased the infarct volume and increased the survival of neuronal cells in the ischemic penumbra; furthermore, DZXI modulated the mitochondrial respiratory chain process and preserved the mitochondrial structure in the brain tissue. Overall, our data suggested that the administration of DZXI is effective at ameliorating neurological and cognitive impairments in AIS, and the underlying mechanisms are related to the protective effects of DZXI on cerebral neurons and neuronal mitochondria.


Increased incidence of BK virus viraemia among patients undergoing chronic haemodialysis: a case-control study.
Incidence of BK virus (BKV) viraemia, a major risk factor for nephropathy, among patients undergoing chronic haemodialysis remains poorly investigated. This case-control study evaluated the risk of infection by BKV, in addition to hepatitis C virus (HCV) among haemodialysis subjects (n=100), compared with age-matched controls (n=100). Subjects' blood plasma samples were subjected to nucleic acid extraction, followed by real-time PCR to evaluate viraemia by BKV and HCV, while sera samples were subjected to ELISA, to identify IgG seropositivity for HCV. Mean age±SD was 47.8±20.4 and 48.9±17.6 years for the haemodialysis and control groups, respectively. BKV and HCV viraemia was observed among 19% versus 8% (OR 2.38, 95% CI 1.09 to 5.18; p=0.023) and 3% versus 0% (p=0.081) of the haemodialysis and control groups, respectively. Mean BK viral load±SD did not vary significantly among the two groups; 914.8±2868 versus 44.30±74.04 copies/mL for the haemodialysis and control groups, respectively (p=0.4041). HCV seropositivity rates were 6% versus 2% (p=0.149), among the haemodialysis and control groups, respectively. Subjects on haemodialysis may be at increased risk of nephropathy due to increased incidence of BK virus reactivations and may require optimisation of immunosuppressive therapy.


Myocardial ischemic-reperfusion injury in a rat model of metabolic syndrome.
Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension.