Differences in trauma team activation criteria among Norwegian hospitals.
To ensure the rapid and correct triage of patients in potential need of specialized treatment, Norwegian hospitals are expected to establish trauma teams with predefined criteria for their activation. The objective of this study was to map and describe the criteria currently in use. We undertook a cross-sectional survey in the summer of 2008, using structured telephone interviews to all Norwegian hospitals that might admit severely injured patients. Forty-nine hospitals were included, of which 48 (98%) had a trauma team and 20 had a hospital-based trauma registry. Criteria for trauma team activation were found at 46 (94%) hospitals. No single criterion was common to all hospitals. The median number of criteria per hospital was 23 (range 8-40), with a total number of 156 and wide variation with respect to physiological "cut-off" values. The mechanism of injury was commonly in use despite a well-known, large over-triage rate. In recent years, Norwegian hospitals have gradually established trauma teams and criteria for their activation. These criteria show considerable variation, including physiological "cut-off" values.


Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies, with continuously increasing cases and fatalities. Diagnosis often occurs in the advanced stages, confining patients to systemic therapies such as sorafenib. Sorafenib (SB), a multi-kinase inhibitor, has not yet demonstrated sufficient efficacy against advanced HCC. There is a strong argument in favor of studying its use in combination with other medications to optimize the therapeutic results. According to our earlier work, crocin (CR), a key bioactive component of saffron, hinders HCC development and liver cancer stemness. In this study, we investigated the therapeutic use of CR or its combination with SB in a cirrhotic rat model of HCC and evaluated how effectively SB and CR inhibited tumor growth in this model. Diethylnitrosamine (DEN) was administered intraperitoneally to rats once a week for 15 weeks, leading to cirrhosis, and then 19 weeks later, leading to multifocal HCC. After 16 weeks of cancer induction, CR (200 mg/kg daily) and SB (10 mg/kg daily) were given orally to rats for three weeks, either separately or in combination. Consistently, the combination treatment considerably decreased the incidence of dyschromatic nodules, nodule multiplicity, and dysplastic nodules when compared to the HCC group of single therapies. Combined therapy also caused the highest degree of apoptosis, along with decreased proliferating and β-catenin levels in the tumor tissues. Additionally, when rats received combined therapy with CR, it showed anti-inflammatory characteristics where nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (Cox-2) were considerably and additively lowered. As a result, CR potentiates the suppressive effects of SB on tumor growth and provides the opportunity to strengthen the therapeutic effects of SB in the treatment of HCC.


Differences in relative and absolute effectiveness of oral P2Y 12 inhibition in men and women: a meta-analysis and modelling study.
To estimate the absolute treatment effects of newer P2Y12 inhibitors (ticagrelor and prasugrel) compared with clopidogrel in men and women with acute coronary syndrome (ACS). We searched Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for randomised controlled trials of oral P2Y12 inhibitors for acute stroke or ACS. Age-specific and sex-specific mortality was obtained for all patients admitted to hospital with myocardial infarction in Scotland from 2006 to 2010 (prior to introduction of prasugrel or ticagrelor). From 9277 articles, nine fulfilled our inclusion criteria. Three trials compared newer P2Y12 inhibitors to clopidogrel in ACS, in which the treatment rate ratio (RR) for major adverse cardiovascular events in men was 0.80 (95% CI 0.69 to 0.93). For the same outcome, across all nine trials, the sex-treatment interaction RR was 1.08 (95% CI 0.98 to 1.19). Combining these estimates yielded a treatment RR in women of 0.86 (95% CI 0.72 to 1.04).17 842 women and 27 818 men were admitted to hospital with myocardial infarction. Mortality was higher for women than men for all-cause (5708, 32.0% vs 5891, 21.2%), cardiovascular (4032, 22.6% vs 4117, 14.8%) and bleeding (193, 1.1% vs 228, 0.8%) deaths.On applying the sex-specific RRs to this population, the absolute risk reduction for mortality at 1 year was similar for women and men for all-cause (2.30% (95% CI -0.92% to 5.22%) vs 2.47% (95% CI 0.62% to 4.10%)), cardiovascular (2.70% (95% CI -0.63% to 5.74%)) vs 2.72% (95% CI 0.92% to 4.35%)) and bleeding (-0.27% (95% CI -1.06% to 0.30%) vs -0.18% (95% CI -0.71% to 0.24%)) deaths. Newer P2Y12 inhibitors may be slightly less efficacious in women than men, but the absolute risk reduction is similar in both sexes.


In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm.
With the rapid spread of antimicrobial resistance in Gram-negative pathogens, biofilm-associated infections are increasingly harder to treat and combination therapy with colistin has become one of the most efficient therapeutic strategies. Our study aimed to evaluate the potential for the synergy of colistin combined with CHIR-090, a potent LpxC inhibitor, against in vitro and in vivoPseudomonas aeruginosa biofilms. Four P. aeruginosa isolates with various colistin susceptibilities were chosen for evaluation. The tested isolates of P. aeruginosa exhibited MIC values ranging from 1 to 64 and 0.0625 to 0.5 μg/ml for colistin and CHIR-090, respectively. Against 24-h static biofilms, minimum biofilm eradication concentration values ranged from 256 to 512 and 8 to >128 μg/ml for colistin and CHIR-090, respectively. Interestingly, subinhibitory concentrations of CHIR-090 contributed to the eradication of subpopulations of P. aeruginosa with the highest colistin MIC values. The combination of colistin and CHIR-090 at subinhibitory concentrations demonstrated synergistic activity both in vivo and in vitro and prevented the formation of colistin-tolerant subpopulations in in vitro biofilms. In summary, our study highlights the in vivo and in vitro synergistic activity of the colistin and CHIR-090 combination against both colistin-susceptible and -nonsusceptible P. aeruginosa biofilms. Further studies are warranted to investigate the clinical relevance of the combination of these two antimicrobials and outline the underlying mechanism for their synergistic action.


Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex immune trait variants using single nucleus ATAC-seq in peripheral blood.
Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 13 individuals. Clustering chromatin accessibility profiles of 96,002 total nuclei identified 17 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type using individuals of European ancestry which identified 6,901 caQTLs at FDR < .10 and 4,220 caQTLs at FDR < .05, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,941 caQTLs we further annotated putative target genes of variant activity using single cell co-accessibility, and caQTL variants were significantly correlated with the accessibility level of linked gene promoters. We fine-mapped loci associated with 16 complex immune traits and identified immune cell caQTLs at 622 candidate causal variants, including those with cell type-specific effects. At the 6q15 locus associated with type 1 diabetes, in line with previous reports, variant rs72928038 was a naïve CD4+ T cell caQTL linked to BACH2 and we validated the allelic effects of this variant on regulatory activity in Jurkat T cells. These results highlight the utility of snATAC-seq for mapping genetic effects on accessible chromatin in specific cell types.


Psychometric validation of a new measurement instrument for time-oriented patient information in electronic medical records: A questionnaire survey of physicians.
Time is an important element in medical data. Physicians record and store information about patients' disease progress and treatment response in electronic medical records (EMRs). Because EMRs use timestamps, physicians can identify patterns over time regarding a patient's disease and treatment (eg, laboratory values and medications). However, analyses of physicians' use and satisfaction with EMRs have focused on functionality, storage, and system operation rather than the use of time-oriented information. This study aimed to understand physicians' needs regarding time-oriented patient information in EMRs in clinical practice. The reliability and validity of the items in the questionnaire were evaluated in 87 physicians at a national university hospital. Internal consistency was satisfactory (Cronbach alpha coefficient, 0.87). Four dimensions were identified in exploratory factor analysis. Correlations between the 4 dimensions supported the construct validity of the items. Scores of time-oriented patients' medical history in the 4 dimensions showed a significant association with physician age. Based on confirmatory factor analysis, associations were significant and positive (P < .001). In terms of the needs of physicians regarding time-oriented patient information in EMRs, both time-oriented treatment results followed by time-oriented team information had significant positive associations. Our study suggests that 4 specific time-oriented patient information factors in EMRs are needed by physicians. Exploring physicians' needs regarding patient-specific time-oriented information may provide a better understanding of the barriers facing the adoption and use of EMRs (eg, decision-making and practice safety concerns) and lead to better acceptance of EMRs in physicians' clinical practices.


Short-form nutrition assessment in patients with advanced heart failure evaluated for ventricular assist device placement or cardiac transplantation.
It has been shown that malnutrition affects clinical outcomes in patients with advanced heart failure and that nutrition status, as determined by the Mini Nutritional Assessment (MNA), can be used as an independent predictor of mortality. The aim of this study was to evaluate the prognostic utility of the short-form MNA (MNA-SF) as a surrogate to the MNA in patients with advanced heart failure. Data retrospectively gathered from nutrition assessments of 162 patients were analyzed. As defined by the MNA, the cohort included 40 (24.7%) patients classified as malnourished, 106 (65.4%) classified as at risk, and 16 (9.9%) classified as well nourished. The mortality for the groups was 37.3%, 47.4%, and 40.5%, respectively. A linear regression showed strong correlation between the MNA and MNA-SF (r = 0.778, P < .0001). A significant difference was observed in survival between the undernourished state (at risk + malnourished) and the well-nourished state, as determined by the MNA-SF (P < .001). The MNA-SF is a rapid nutrition assessment that correlates strongly with the full-form MNA and is an independent predictor of mortality.


Education, night splinting and exercise versus usual care on recovery and conversion to surgery for people awaiting carpal tunnel surgery: a protocol for a randomised controlled trial.
Carpal tunnel syndrome (CTS) is a prevalent upper limb condition that results in significant individual and socioeconomic costs. Large patient numbers, long outpatient waiting times and traditional referral pathways in public health systems create delays in accessing treatment for this condition. Alternative care pathways aimed at streamlining access to treatment and reducing the need for surgical intervention warrant further investigation. A randomised, single-blind controlled clinical trial will be conducted. 128 participants aged 18-75 years with CTS will be recruited from the carpal tunnel surgery waitlists of participating public hospitals. Suitable participants will be stratified for severity and randomly allocated to either receive therapy (education, provision of splints and a home exercise programme) or standard care (continuing on the waitlist without hand therapy intervention for the duration of the study). Outcomes will be measured at baseline and after 6 weeks and 6 months. Primary outcomes are conversion to surgery ratio and perceived effect via the Global Rating of Change Scale.Secondary measures include patient satisfaction, and monitoring of symptoms and function using outcome measures including the Boston CTS Questionnaire, Disability of Arm, Shoulder and Hand Questionnaire, Patient-Specific Functional Scale, patient completed diagram of symptoms and Self-reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale. This paper outlines the design and rationale for a randomised controlled trial that aims to assess the efficacy of an alternative care pathway for the management of patients with CTS while on the surgery waitlist. It is anticipated that the outcomes of this study will contribute to improved and expedited management of this common condition in a public hospital setting. Ethics approval was granted by the Princess Alexandra Hospital Centres for Health Research (HREC/13/QPAH/434-SSA/13/QPAH/447) and the Medical Research Ethics Committee at the University of Queensland. Results will be disseminated via conferences and peer-reviewed publications. ACTRN12613001095752.


Subjective agency and awareness of shared actions.
Voluntary actions and their distal effects are intimately related in conscious awareness. When an expected effect follows a voluntary action, the experience of the interval between these events is compressed in time, a phenomenon known as 'intentional binding' (IB). Current accounts of IB suggest that it serves to reinforce associations between our goals and our intention to attain these goals via action, and that IB only occurs for self-generated (i.e., intentional) actions. We used a novel approach to study IB in the context of shared intentions and actions. Pairs of participants judged the time of occurrence of actions and events attributed either to oneself or to another agent. We found that IB and subjective agency are not mutually predictive when an action can be attributed to only one of two 'co-intending' agents. Our results pose a complication for the prevailing view that IB and subjective agency reflect a common mechanism.


Lifetime history of major depression predicts the development of the metabolic syndrome in middle-aged women.
To prospectively examine the association of major depression with incidence of the metabolic syndrome in women. Data were drawn from one of seven sites of the Study of Women's Health Across the Nation (SWAN), a prospective cohort study of the menopausal transition. Participants were 429 (34.5% African-American) women. Major depression and comorbid diagnoses were assessed via the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Axis I Disorders at baseline and seven annual follow-up evaluations. The metabolic syndrome was measured at baseline and each follow-up evaluation (except the second) based on National Cholesterol Education Program (NCEP) criteria. Longitudinal generalized estimating equations (GEE) models indicated that, in women who were free of the metabolic syndrome at baseline, a lifetime major depression history or current major depressive episode at baseline was significantly associated with the onset and presence of the metabolic syndrome during the follow-up (odds ratio = 1.82; 95% Confidence Interval (CI) = 1.06-3.14). Survival analyses showed that, in women who were free of the metabolic syndrome at baseline, a lifetime major depression history or current major depressive episode at baseline predicted increased risk of developing the metabolic syndrome during the follow-up (hazard ratio = 1.66; 95% CI = 0.99-3.75). Lifetime history of alcohol abuse or dependence predicted incident metabolic syndrome and attenuated the association between depression and the metabolic syndrome in both models. This study documents that major depression is a significant predictor of the onset of the metabolic syndrome. Intervention studies targeting depression may prevent the development of the metabolic syndrome in women.


Screen-Printed Electroluminescent Lamp Modified with Graphene Oxide as a Sensing Device.
A screen-printed electroluminescent display with different sensing capabilities is presented. The sensing principle is based on the direct relationship between the light intensity of the lamp and the conductivity of the external layers. The proposed device is able to detect the ionic concentration of any conductive species. Using both top and bottom emission architectures, for the first time, a humidity sensor based on electroluminescent display functionalized by a graphene oxide nanocomposite is introduced. In this regard, just by coupling the display to a smartphone camera sensor, its potential was expanded for automatically monitoring human respiration in real time. Besides, the research includes a responsive display in which the light is spatially turned on in response to pencil drawing or any other conductive media. The above mentioned features together with the easiness of manufacturing and cost-effectiveness of this electroluminescent display can open up great opportunities to exploit it in sensing applications and point-of-care diagnosis.


CD95/Fas, Non-Apoptotic Signaling Pathways, and Kinases.
Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate. The receptor CD95 (also named Fas or apoptosis antigen 1) belongs to the tumor necrosis factor (TNF) receptor superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Because mutations of this receptor or its ligand lead to autoimmune disorders such as systemic lupus erythematosus (SLE) and cancers, CD95 and CD95L were initially thought to play a role in immune homeostasis and tumor elimination via apoptotic signaling pathways. However, recent data reveal that CD95 also evokes non-apoptotic signals, promotes inflammation, and contributes to carcinogenesis; therefore, it is difficult to dissect its apoptotic effects from its non-apoptotic effects during pathogenesis of disease. CD95L is cleaved by metalloproteases and so exists in two different forms: a transmembrane form and a soluble ligand (s-CD95L). We recently observed that the soluble ligand is overexpressed in serum from patients with triple-negative breast cancer or SLE, in whom it contributes to disease severity by activating non-apoptotic signaling pathways and promoting either metastatic dissemination or accumulation of certain T cell subsets in damaged organs. Here, we discuss the roles of CD95 in modulating immune functions via induction of mainly non-apoptotic signaling pathways.


[HBSC study on young adolescents' health behaviours: some insights for practitioners].
Lifestyle choices exert a major influence over the present and future health of adolescents. The international study "Health Behaviour in School-aged Children (HBSC)" was created to monitor the social determinants, the health and risk behaviours, and the protective and adverse factors that each influence young adolescents' health. The survey is conducted every four years, and the WHO produced its latest edition in the spring of 2012 (using the 2010 data). We have selected and summarised what seem to be the most important insights for Swiss clinicians. The overall results are satisfactory but some weaknesses remind us that prevention is an ongoing challenge both in private practices and in public policy.


Triiodothyronine control of ATP-citrate lyase and malic enzyme during differentiation of a murine preadipocyte cell line.
In the Ob 17 preadipocyte cell line, during adipose differentiation, T3 amplified the progressive expression of two enzymes of the lipogenic pathway, ATP-citrate lyase (ATP-CL) and malic enzyme (ME) as previously described for fatty acid synthase (FAS) and fatty acid synthesis, and in the same time-period of development. However, the stimulation by T3 was sustained at late stages of differentiation whereas it declined in FAS studies. The stimulation was preceded by an increase in the relative abundance of the specific mRNAs. Two ME mRNA species were detected (21S and 27S) and found to be differently distributed. Their abundance was asynchronously increased by T3 with a predominant effect on the 21S species. Culture of the cells in a thyroid-hormone depleted medium prevented any significant increase of ME activity. Early inclusion of T3 largely restored ME development whereas late elimination of T3 only moderately impaired it. It is suggested that T3 plays a crucial role at an early step of adipose differentiation, this leading to an increased expression of a set of late adipose phenotypes such as several lipogenic enzymes.


Grit Is Associated with Structure of Nucleus Accumbens and Gains in Cognitive Training.
There is a long-standing interest in the determinants of successful learning in children. "Grit" is an individual trait, reflecting the ability to pursue long-term goals despite temporary setbacks. Although grit is known to be predictive of future success in real-world learning situations, an understanding of the underlying neural basis and mechanisms is still lacking. Here we show that grit in a sample of 6-year-old children (n = 55) predicts the working memory improvement during 8 weeks of training on working memory tasks (p = .009). In a separate neuroimaging analysis performed on a partially overlapping sample (n = 27), we show that interindividual differences in grit were associated with differences in the volume of nucleus accumbens (peak voxel p = .021, x = 12, y = 11, z = -11). This was also confirmed in a leave-one-out analysis of gray matter density in the nucleus accumbens (p = .018). The results can be related to previous animal research showing the role of the nucleus accumbens to search out rewards regardless of delays or obstacles. The results provide a putative neural basis for grit and could contribute a cross-disciplinary connection of animal neuroscience to child psychology.


[The ultrastructure of anaerobes isolated from the urogenital tract of women].
Electron microscopic (ultrathin sections) examination of culture strains of vaginal Gardnerella and bacteroids isolated in aerobic conditions from urogenital tract of women suffering from Gardnerella infection was carried out. Structural analysis of the bacteria is presented, i.e. their shape, size, morphology, and features of multiplication.


Increased Mortality in Hip Fracture Patients Living Alone: A NOREPOS Study.
Hip fracture is associated with excess mortality, persisting for many years after the fracture. Several factors may affect survival; however, the role of social support has been less studied. Living situation could be an indicator of a person's social support, which predicts mortality in the general population. In this longitudinal cohort study, we considered whether living alone was a risk factor for post-hip fracture mortality compared with living with a partner. Information on hip fractures from all hospitals in Norway from 2002 to 2013 was combined with the 2001 National Population and Housing Census. The association between living situation and mortality during 12.8 years of follow-up in 12,770 men and 22,067 women aged 50 to 79 years at fracture was investigated using flexible parametric survival analysis. We also estimated relative survival of hip fracture patients compared with that of the non-fractured background population in the same living situation (alone or with a partner). Higher mortality after hip fracture was found in both men and women living alone versus with a partner (hazard ratio [HR] men = 1.37, 95% confidence interval [CI] 1.29-1.44; HR women = 1.23, 95% CI 1.18-1.28, adjusting for age, education level, urbanization degree, and number of children). We demonstrated the strongest association in male hip fracture patients aged <60 years (long-term mortality HR = 3.29, 95% CI 2.25-6.49). Compared with the general population, relative survival 8 years after a hip fracture was 43% in men and 61% in women living alone, whereas relative survival in those living with a partner was 51% in men and 67% in women. In conclusion, hip fracture patients who lived alone had higher mortality than those living with a partner and lower survival relative to the general population. © 2021 American Society for Bone and Mineral Research (ASBMR).


Ni(II)-decorated porous titania microspheres as a stationary phase for column chromatography applications: Highly selective purification of hemoglobin from human blood.
Titania (TiO2)-based monodisperse-porous stationary phase/sorbent was synthesized by decoration of Ni(II) ions onto TiO2 microspheres 4.2 µm in size, obtained by a staged-shape template hydrolysis and condensation protocol. Ni(II) ions were attached onto iminodiacetic acid-3-glycidoxypropyltrimethoxysilane (IDA-GPTMS) bound-titania microspheres by metal-chelate complex formation. The appropriate mean size, sufficiently high surface area and high porosity providing an appropriate column permeability make Ni(II)-decorated TiO2 microspheres a good sorbent/stationary phase for batch/continuous-column chromatography applications. Ni(II)-decorated TiO2 microspheres were investigated as a sorbent for purification of a typical histidine-rich protein, hemoglobin (Hb) via immobilized metal affinity chromatography (IMAC) in batch fashion, by including bovine serum albumin (BSA) as reference. The saturation capacities of batch adsorption runs performed with bovine Hb and BSA were determined as 137 ± 9 and 45 ± 3 mg/g, respectively. Human Hb with the purity of > 95% was recovered from whole blood by IMAC conducted in batch-fashion. Ni(II)-decorated microspheres were also evaluated as a stationary phase in a microfluidic-IMAC system, in which, human Hb was recovered from whole blood with a purity of 85%. The microfluidic-IMAC system constructed here, based on monodisperse-porous TiO2 microspheres, is a promising tool for genomics/proteomics applications involving isolation of valuable biomolecules from low-volume samples.


Convergence between observations and interviews in clinical diagnosis of reactive attachment disorder and disinhibited social engagement disorder.
A comprehensive approach is needed for diagnosing disordered attachment behavior due to the multifaceted nature of attachment. Differences between various indicators can pose a challenge for deciding on the proper diagnosis. This study assessed the convergence between clinical interview assessment and observation-based clinical diagnosis, and their linkages with inadequate care. Participating children ( N = 55) had intelligence quotients (IQs) between 50 and 85 and were referred for psychiatric consultation. Data were obtained by structured review of medical records, the Disturbances of Attachment Interview (DAI), and the Clinical Observation of Attachment (COA) procedure. Of the 18 children identified using the DAI with Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) diagnosis of reactive attachment disorder (RAD) and/or disinhibited social engagement disorder (DSED), only 7 received a clinical DSM-5 diagnosis of RAD and/or DSED. Observed maladaptive attachment behavior in the COA was strongly associated with DAI scores and with clinical diagnosis of DSM-5 RAD and/or DSED. There was a significantly higher prevalence of extremes of insufficient care in children who were classified with RAD by DAI or DSM-5 and/or with DSED by DSM-5 compared to those with no attachment disorder. Using structured observation and record assessment leads to more conservative identification of RAD or DSED than using the DAI.


Particulate copper electrodeposited on carbon felt for degradation of low concentration of methyl iodide in liquid radioactive wastes.
In this work, the study of copper particles deposition on to carbon felt was presented by pulse electrodeposition method to electrochemically degrade methyl iodide (CH3I, 1 mg L-1) in aqueous solution. In order to solve the problems linked to the heterogeneous potential distribution in the 3-D porous structure, which lead to the so-called 'black core', we successfully used low concentration of copper salt (1 mM) and negative deposition potential (-2.5 V) to obtain Cu-nanoparticles/carbon felt (Cu-nano/CF) electrode, the copper coating improved the specific surface area of carbon felt from ∼0.07 to 0.7 m2 g-1 with high catalytic activity. Results show that 98.1% of CH3I can be removed with the Cu-nano/CF electrode in 120 min.


Separate measurements of surface shapes and refractive index inhomogeneity of an optical element using tunable-source phase shifting interferometry.
A phase shifting interferometer using a tunable laser as a light source is proposed for measuring shapes of both surfaces of a glass plate and the distribution of refractive index. To separate the superimposed interferograms generated with many wavefronts reflected from the plate, the phase shift associated with the wavelength shift is applied in the phase shifting interferometer with unequal optical paths in testing and reference beams. A laser diode is used for the tunable light source, and the data processing for obtaining phase distribution is based on the least-squares fitting in interferograms. The rms errors of the measurements are <1/50 wavelength for the surface shape, and 10(-5) of the refractive index for a 5-mm thick optical glass plate.


Antioxidants in health and disease.
Free radical production occurs continuously in all cells as part of normal cellular function. However, excess free radical production originating from endogenous or exogenous sources might play a role in many diseases. Antioxidants prevent free radical induced tissue damage by preventing the formation of radicals, scavenging them, or by promoting their decomposition. This article reviews the basic chemistry of free radical formation in the body, the consequences of free radical induced tissue damage, and the function of antioxidant defence systems, with particular reference to the development of atherosclerosis.


Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder.
GABA(A) receptors play an important regulatory role in the developmental events leading to the formation of complex neuronal networks and to the behaviors they govern. The primary aim of this study was to assess whether gabrb3 gene deficient (gabrb3(-/-)) mice exhibit abnormal social behavior, a core deficit associated with autism spectrum disorder. Social and exploratory behaviors along with non-selective attention were assessed in gabrb3(-/-), littermates (gabrb3(+/+)) and progenitor strains, C57BL/6J and 129/SvJ. In addition, semi-quantitative assessments of the size of cerebellar vermal lobules were performed on gabrb3(+/+) and gabrb3(-/-) mice. Relative to controls, gabrb3(-/-) mice exhibited significant deficits in activities related to social behavior including sociability, social novelty and nesting. In addition, gabrb3(-/-) mice also exhibited differences in exploratory behavior compared to controls, as well as reductions in the frequency and duration of rearing episodes, suggested as being an index of non-selective attention. Gabrb3(-/-) mice also displayed significant hypoplasia of the cerebellar vermis compared to gabrb3(+/+) mice. The observed behavioral deficits, especially regarding social behaviors, strengthens the face validity of the gabrb3 gene deficient mouse as being a model of autism spectrum disorder.


Timing and Weather Offer Alternative Mitigation Strategies for Lowering Bat Mortality at Wind Energy Facilities in Ontario.
Relatively high mortality of migratory bats at wind energy facilities has prompted research to understand the underlying spatial and temporal factors, with the goal of developing more effective mitigation approaches. We examined acoustic recordings of echolocation calls at 12 sites and post-construction carcass survey data collected at 10 wind energy facilities in Ontario, Canada, to quantify the degree to which timing and regional-scale weather predict bat activity and mortality. Rain and low temperatures consistently predicted low mortality and activity of big brown bats (Eptesicus fuscus) and three species of migratory tree bats: hoary bat (Lasiurus cinereus), eastern red bat (L. borealis), and silver-haired bat (Lasionycteris noctivagans). Bat activity occurred in waves with distinct peaks through the season; regardless of seasonal timing, most activities occurred in the first half of the night. We conclude that wind energy facilities could adopt a novel and more effective curtailment strategy based on weather and seasonal and nocturnal timing that would minimize mortality risks for bats while increasing the opportunities for power generation, relative to the mitigation strategy of increasing cut-in wind speed to 5.5 m/s.


Charge transfer excitations from particle-particle random phase approximation-Opportunities and challenges arising from two-electron deficient systems.
The particle-particle random phase approximation (pp-RPA) is a promising method for studying charge transfer(CT) excitations. Through a detailed analysis on two-electron deficient systems, we show that the pp-RPA is always able to recover the long-distance asymptotic -1/R trend for CT excitations as a result of the concerted effect between orbital energies and the pp-RPA kernel. We also provide quantitative results for systems with relatively short donor-acceptor distances. With conventional hybrid or range-separated functionals, the pp-RPA performs much better than time-dependent density functional theory (TDDFT), although it still gives underestimated results which are not as good as TDDFT with system-dependent tuned functionals. For pp-RPA, there remain three great challenges in dealing with CT excitations. First, the delocalized frontier orbitals in strongly correlated systems often lead to difficulty with self-consistent field convergence as well as an incorrect picture with about half an electron transferred. Second, the commonly used density functionals often underestimate the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (LUMO) for the two-electron deficient species, resulting in systems with delocalized orbitals. Third, the performance of pp-RPA greatly depends on the energy difference between the LUMO and a higher virtual orbital. However, the meaning of the orbital energies for higher virtual orbitals is still not clear. We also discuss the performance of an approximate pp-RPA scheme that uses density functional tight binding (pp-DFTB) as reference and demonstrate that the aforementioned challenges can be overcome by adopting suitable range-separated hybrid functionals. The pp-RPA and pp-DFTB are thus promising general approaches for describing charge transfer excitations.


Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5.
The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization.


Diagnostic conundrum of oppositional defiant disorder and conduct disorder.
Evidence for a diagnostic distinction of oppositional defiant disorder (ODD) and conduct disorder (CD) is reviewed, and alternative conceptualizations and definitions for the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders are considered. Studies suggest that CD and ODD are strongly and developmentally related but clearly different. Factor analyses indicate that distinct covarying groups of ODD and CD symptoms can be identified, but certain symptoms relate to both (particularly mild aggression and lying). Age of onset for ODD is earlier than for most CD symptoms. Nearly all youths with CD have a history of ODD, but not all ODD cases progress to CD. The disorders demonstrate the same forms of parental psychopathology and family adversity but to a greater degree for CD than for ODD. Alternative conceptualizations for the disorders are presented for further study before the introduction of the DSM-IV.


Evaluating an admission avoidance pathway for children in the emergency department: outpatient intravenous antibiotics for moderate/severe cellulitis.
Children with moderate/severe cellulitis requiring intravenous antibiotics are usually admitted to hospital. Admission avoidance is attractive but there are few data in children. We implemented a new pathway for children to be treated with intravenous antibiotics at home and aimed to describe the characteristics of patients treated on this pathway and in hospital and to evaluate the outcomes. This is a prospective, observational cohort study of children aged 6 months-18 years attending the ED with uncomplicated moderate/severe cellulitis in March 2014-January 2015. Patients received either intravenous ceftriaxone at home or intravenous flucloxacillin in hospital based on physician discretion. Primary outcome was treatment failure defined as antibiotic change within 48 hours due to inadequate clinical improvement or serious adverse events. Secondary outcomes include duration of intravenous antibiotics and complications. 115 children were included: 47 (41%) in the home group and 68 (59%) in the hospital group (59 hospital-only, 9 transferred home during treatment). The groups had similar clinical features. 2/47 (4%) of the children in the home group compared with 8/59 (14%) in the hospital group had treatment failure (P=0.10). Duration of intravenous antibiotics (median 1.9 vs 1.8 days, P=0.31) and complications (6% vs 10%, P=0.49) were no different between groups. Home treatment costs less, averaging $A1166 (£705) per episode compared with $A2594 (£1570) in hospital. Children with uncomplicated cellulitis may be able to avoid hospital admission via a home intravenous pathway. This approach has the potential to provide cost and other benefits of home treatment.


CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.


Outcomes of PCI at hospitals with or without on-site cardiac surgery.
Performance of percutaneous coronary intervention (PCI) is usually restricted to hospitals with cardiac surgery on site. We conducted a noninferiority trial to compare the outcomes of PCI performed at hospitals without and those with on-site cardiac surgery. We randomly assigned participants to undergo PCI at a hospital with or without on-site cardiac surgery. Patients requiring primary PCI were excluded. The trial had two primary end points: 6-week mortality and 9-month incidence of major adverse cardiac events (the composite of death, Q-wave myocardial infarction, or target-vessel revascularization). Noninferiority margins for the risk difference were 0.4 percentage points for mortality at 6 weeks and 1.8 percentage points for major adverse cardiac events at 9 months. A total of 18,867 patients were randomly assigned in a 3:1 ratio to undergo PCI at a hospital without on-site cardiac surgery (14,149 patients) or with on-site cardiac surgery (4718 patients). The 6-week mortality rate was 0.9% at hospitals without on-site surgery versus 1.0% at those with on-site surgery (difference, -0.04 percentage points; 95% confidence interval [CI], -0.31 to 0.23; P=0.004 for noninferiority). The 9-month rates of major adverse cardiac events were 12.1% and 11.2% at hospitals without and those with on-site surgery, respectively (difference, 0.92 percentage points; 95% CI, 0.04 to 1.80; P=0.05 for noninferiority). The rate of target-vessel revascularization was higher in hospitals without on-site surgery (6.5% vs. 5.4%, P=0.01). We found that PCI performed at hospitals without on-site cardiac surgery was noninferior to PCI performed at hospitals with on-site cardiac surgery with respect to mortality at 6 weeks and major adverse cardiac events at 9 months. (Funded by the Cardiovascular Patient Outcomes Research Team [C-PORT] participating sites; ClinicalTrials.gov number, NCT00549796.).


Novel interactions between mitochondrial superoxide dismutases and the electron transport chain.
The processes that control aging remain poorly understood. We have exploited mutants in the nematode, Caenorhabditis elegans, that compromise mitochondrial function and scavenging of reactive oxygen species (ROS) to understand their relation to lifespan. We discovered unanticipated roles and interactions of the mitochondrial superoxide dismutases (mtSODs): SOD-2 and SOD-3. Both SODs localize to mitochondrial supercomplex I:III:IV. Loss of SOD-2 specifically (i) decreases the activities of complexes I and II, complexes III and IV remain normal; (ii) increases the lifespan of animals with a complex I defect, but not the lifespan of animals with a complex II defect, and kills an animal with a complex III defect; (iii) induces a presumed pro-inflammatory response. Knockdown of a molecule that may be a pro-inflammatory mediator very markedly extends lifespan and health of certain mitochondrial mutants. The relationship between the electron transport chain, ROS, and lifespan is complex, and defects in mitochondrial function have specific interactions with ROS scavenging mechanisms. We conclude that mtSODs are embedded within the supercomplex I:III:IV and stabilize or locally protect it from reactive oxygen species (ROS) damage. The results call for a change in the usual paradigm for the interaction of electron transport chain function, ROS release, scavenging, and compensatory responses.


A multivariate prediction model and its application in forecasting acute ischemic stroke: Protocol for a retrospective clinical study.
Acute ischemic stroke (AIS) occurs due to brain ischemia as a result of thrombosis of a cerebral blood vessel. It is a common cerebral blood circulation disorder worldwide and an important cause of death and disability. This study aims to establish a prediction model of multiple single category indicators and a joint model, through which to plot multiple receiver operating characteristic curves and compare area under curve of the models so as to predict the occurrence of AIS, explore the pathogenesis of AIS, and provide reference for clinical diagnosis and treatment of AIS. A retrospective clinical study was conducted in a Level A tertiary hospital in Sichuan Province, China. The patients participated in this study were over 18 years of age and suffered from acute ischemic stroke. They were hospitalized in department of neurology from October 1, 2019 to September 30, 2022, and underwent coronary artery computed tomographic arteriography (CTA) and blood biomarker detection. We collected demographic information, CTA data and blood biomarker detection values of all these patients. Through analyzing the clinical data of high-risk groups, this study provides guidance for the prevention and treatment of AIS, and promote further research.


Vasopressin, gonadal steroids and social recognition.
Rodents exposed for a short amount of time to conspecific juveniles spend less time investigating familiar than unfamiliar juveniles. This is based on the formation of an olfactory image of juveniles, which involves an androgen-dependent vasopressinergic pathway in males, as demonstrated by the ability of the vasopressin receptor antagonist dPTyr(Me)VP to block social recognition in intact male but not in female and castrated rats and mice. The involvement of sexually dimorphic vasopressinergic neurons appears to be dependent on the processing of social olfactory cues by the vomeronasal organ since removal of this organ in male rats mimics the effects of castration. These findings are discussed in relation to the role of vasopressin in learning and memory.


Association of Sperm Aneuploidy Frequency and DNA Fragmentation Index in Infertile Men.
For improving the evaluation of male infertility, many parameters were studied and reported in earlier literature. The aim of this study was to estimate the frequency of sperm aneuploidy and DNA fragmentation in infertile men and to assess the correlation between sperm aneuploidy and DNA fragmentation. In this study 100 infertile men were included, cases with azoospermia were 68%, oligospermia 18%, severe oligospermia 6%, and oligoasthenoteratospermia (OAT) 8%. Ten normozoospermic men who had two normal children were included as a control. The sperm aneuploidy test by Fluorescence In Situ Hybridization (FISH) and sperm DNA fragmentation index by TdT (Terminal deoxynucleotidyl transferase)-mediated dUTP nick end labelling (TUNEL) were carried out. To determine the aneuploidy status and DNA fragmentation index, frequency was used. The correlation between sperm aneuploidy and sperm DNA fragmentation along with age was assessed by using Spearman's correlation coefficient. The p<0.05 was considered significant. The age of 100 subjects ranged between 22-48 years (35.5±5.1). Sperm aneuploidy frequency and DNA fragmentation rate were found to be higher in infertile men compared to control men (n=10). There was a significant relationship between age and sex chromosomal aneuploidy (p<0.05) and significant difference between sperm aneuploidy and damaged DNA (p<0.05). FISH and TUNEL assay results showed increased sperm aneuploidy frequency, and DNA fragmentation index in infertile men compared with the fertile men. There is significant relationship observed between sperm aneuploidy and DNA fragmentation. These two parameters are important and they must be investigated for clinical practice.


Nutritional regulation of stem and progenitor cells in Drosophila.
Stem cells and their progenitors are maintained within a microenvironment, termed the niche, through local cell-cell communication. Systemic signals originating outside the niche also affect stem cell and progenitor behavior. This review summarizes studies that pertain to nutritional effects on stem and progenitor cell maintenance and proliferation in Drosophila. Multiple tissue types are discussed that utilize the insulin-related signaling pathway to convey nutritional information either directly to these progenitors or via other cell types within the niche. The concept of systemic control of these cell types is not limited to Drosophila and may be functional in vertebrate systems, including mammals.


Liposomes in topical drug delivery.
The possible use of liposomes as topical drug delivery vehicles for both water- and lipid-soluble drugs has been investigated. Data for two characteristic drugs, penicillin G and indoxole, are presented. Liposome uptake by the cornea is greatest for positively charged liposomes, less for negatively charged liposomes, and least for neutral liposomes, suggesting that the initial interaction between the corneal surface and liposomes is electrostatic adsorption. Positively charged unilamellar liposomes enhanced transcorneal flux of penicillin G across isolated rabbit cornea more than fourfold. Liposomal entrapment of drug is prerequisite to enhanced transport; corneal penetration was not enhanced when liposomes that were preformed in the absence of drug were mixed with penicillin G immediately before application to the cornea. Although penicillin G is water-soluble, the findings indicate that it secondarily associates with liposome membranes, possibly by insertion of its hydrophobic end into the lipid bilayer. Indoxole, however, was incorporated directly into the membranes of pure phosphatidyl choline liposomes. Liposome-mediated drug flux efficiency after topical instillation in rats was significantly greater than that obtained with equivalent concentration of drug delivered in polysorbate 80. Ten times more drug in polysorbate 80 was required to equal liposome-mediated flux efficiency. The findings suggest that liposomes enhance corneal penetration of drug by adsorbing to the corneal surface, with direct transfer of drug from liposomal to epithelial cell membranes.


Biomarkers of Mineral and Bone Metabolism and 20-Year Risk of Hospitalization With Infection: The Atherosclerosis Risk in Communities Study.
Mineral and bone disorders (MBDs) might be relevant in the etiology of infection. To determine whether MBD biomarkers were associated with the incidence of hospitalization with infection. We also assessed the cross-sectional association between MBD biomarker levels and kidney function. Community-based cohort study of 11,218 participants with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 in the Atherosclerosis Risk in Communities study. We assessed the cross-sectional associations of five MBD markers-fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), calcium corrected for hypoalbuminemia, and phosphorus-with eGFR from 1990 to 1992 and their longitudinal associations with incident hospitalization with infection in 1990 to 2013. Incident hospitalization with infection. In age-, sex-, and race-adjusted models, lower eGFRs were significantly associated with greater levels of FGF23, PTH, and corrected calcium but not 25(OH)D or phosphorus. During follow-up, 5078 hospitalizations with infection occurred. In fully adjusted Cox models, with the second quartile as the reference, the hazard ratio (HR) was significantly greater in the highest quartile of FGF23 [HR, 1.12; 95% confidence interval (CI), 1.03 to 1.21], PTH (HR, 1.09; 95% CI, 1.01 to 1.18), and corrected calcium (HR, 1.11; 95% CI, 1.03 to 1.20), and lowest quartile for 25(OH)D (HR, 1.11; 95% CI, 1.03 to 1.21). The association with phosphorus was significant only when the outcome was restricted to primary diagnosis of infection. These findings were consistent across subgroups of age, sex, race, and eGFR (<60 vs ≥60 mL/min/1.73 m2). MBD biomarkers were associated with eGFR and the subsequent risk of infection, supporting MBD involvement in the etiology of infection.


The effect of whole-body vibration exercise on postmenopausal women with osteoporosis: A protocol for systematic review and meta-analysis.
Osteoporosis (OP) is an age-related disease characterized by reduced bone mass and increased bone fragility. It is more common in older people and postmenopausal women. As a new type of exercise training for OP, whole-body vibration (WBV) exercise has been proved to have a good effect on postmenopausal women with OP. It can increase bone density and improve strength and balance in postmenopausal population, which has certain clinical value, but lacks evidence-based medicine evidence. This study aims to systematically study the effectiveness of WBV exercise on postmenopausal women with OP. The English databases (PubMed, Embase, Web of Science, The Cochrane Library) and Chinese databases (China National Knowledge Network, Wanfang, Weipu, China Biomedical Database) were searched by computer. From the establishment of the database to February 2021, the randomized controlled clinical studies on WBV exercise on postmenopausal women with OP were conducted. The quality of the included studies was independently extracted by 2 researchers and literature quality was evaluated. Meta-analysis of the included studies was performed using RevMan5.3 software. In this study, the efficacy and safety of WBV exercise on postmenopausal women with OP were evaluated by lumbar spine bone density, femoral neck bone density, pain, incidence of falls, incidence of fractures, and quality of life scale score, etc. This study will provide reliable evidences for the clinical application of WBV exercise on postmenopausal women with OP. Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. DOI 10.17605/OSF.IO/WPYT9.


Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response to abiraterone in castration resistant patients.
Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance. The isolated platelet population of blood samples and digital-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis inhibiting therapy. Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-2 and -3 (KLK2, KLK3), folate hydrolase 1 (FOLH1), and neuropeptide-Y (NPY) were uniquely present within the platelet fraction of cancer patients and not detected in healthy controls (n = 15). In the abiraterone treated cohort, the biomarkers provided information on therapy outcome, demonstrating an association between detectable biomarkers and short progression free survival (PFS) (FOLH1, P < 0.01; KLK3, P < 0.05; and NPY, P < 0.05). Patients with biomarker-negative platelets had the best outcome, while FOLH1 (P < 0.05) and NPY (P = 0.05) biomarkers provided independent predictive information in a multivariate analysis regarding PFS. KLK2 (P < 0.01), KLK3 (P < 0.001), and FOLH1 (P < 0.05) biomarkers were associated with short overall survival (OS). Combining three biomarkers in a panel (KLK3, FOLH1, and NPY) made it possible to separate long-term responders from short-term responders with 87% sensitivity and 82% specificity. Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with higher accuracy than baseline serum PSA or PSA response.


Development and validation of a modified comet assay to phenotypically assess nucleotide excision repair.
There is an increasing need for simple and reliable approaches to phenotypically assess DNA repair capacities. Therefore, a modification of the alkaline comet assay was developed to determine the ability of human lymphocyte extracts to perform the initial steps of the nucleotide excision repair (NER) process, i.e. damage recognition and incision. Gel-embedded nucleoids from A549 cells, pre-exposed to 1 microM benzo[a]pyrene-diol-epoxide, were incubated with cell extracts from frozen or freshly isolated lymphocytes. The rate at which incisions are introduced and the subsequent increase in tail moment is indicative for the repair capacity of the extracts. Freshly prepared extracts from lymphocytes of human volunteers (n = 8) showed significant inter-individual variations in their DNA repair capacity, which correlated with the removal of bulky DNA lesions over a period of 48 h determined by (32)P-post-labelling (R(2) = 0.76, P = 0.005). Repeated measurements revealed a low inter-assay variation (11%). Storage of cell extracts for more than 3 weeks significantly reduced (up to 80%) the capacity to incise the damaged DNA as compared to freshly isolated extracts. This reduction was completely restored by addition of ATP to the extracts before use, as it is required for the incision step of NER. In contrast, extracts freshly prepared from frozen lymphocyte pellets can be used without loss of repair activity. DNA repair deficient XPA-/- and XPC-/- fibroblasts were used to further validate the assay. Although some residual capacity to incise the DNA was observed in these cells, the repair activity was restored to normal wild-type levels when a complementary mixture of both extracts (thereby restoring XPA and XPC deficiency) was used. These results demonstrate that this repair assay can be applied in molecular epidemiological studies to assess inter-individual differences in NER.


A randomized controlled trial investigating the value of patient-specific instrumentation for total knee arthroplasty in the Canadian healthcare system.
The purpose of the present study was to compare patient-specific instrumentation (PSI) and conventional surgical instrumentation (CSI) for total knee arthroplasty (TKA) in terms of early implant migration, alignment, surgical resources, patient outcomes, and costs. The study was a prospective, randomized controlled trial of 50 patients undergoing TKA. There were 25 patients in each of the PSI and CSI groups. There were 12 male patients in the PSI group and seven male patients in the CSI group. The patients had a mean age of 69.0 years (sd 8.4) in the PSI group and 69.4 years (sd 8.4) in the CSI group. All patients received the same TKA implant. Intraoperative surgical resources and any surgical waste generated were recorded. Patients underwent radiostereometric analysis (RSA) studies to measure femoral and tibial component migration over two years. Outcome measures were recorded pre- and postoperatively. Overall costs were calculated for each group. There were no differences (p > 0.05) in any measurement of migration at two years for either the tibial or femoral components. Movement between one and two years was < 0.2 mm, indicating stable fixation. There were no differences in coronal or sagittal alignment between the two groups. The PSI group took a mean 6.1 minutes longer (p = 0.04) and used a mean 3.4 less trays (p < 0.0001). Total waste generated was similar (10 kg) between the two groups. The PSI group cost a mean CAD$1787 more per case (p < 0.01). RSA criteria suggest that both groups will have revision rates of approximately 3% at five years. The advantages of PSI were minimal or absent for surgical resources used and waste eliminated, and for meeting target alignment, yet had significantly greater costs. Therefore, we conclude that PSI may not offer any advantage over CSI for routine primary TKA cases. Cite this article: Bone Joint J 2019;101-B:565-572.


Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic.
Human papillomavirus (HPV) testing in urine offers a convenient approach for cervical cancer screening but has previously suffered from limited clinical sensitivity. We evaluated clinical performance of the prototype Trovagene HPV test, a novel polymerase chain reaction assay that targets the E1 region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA in urine. We conducted a pilot study among 72 women referred to colposcopy following abnormal screening. Participants provided a urine sample prior to clinician-collected cervical sampling and colposcopically-directed punch biopsy. Trovagene HPV test results on urine samples were compared with cervical and urine testing by Linear Array HPV Genotyping Test (LA-HPV) for detection of histologically-confirmed cervical precancerous lesions. There was high concordance between urine samples tested by the Trovagene HPV test and corresponding cervical (87.5%) and urine (81.9%) samples tested by LA-HPV. The Trovagene HPV test had high sensitivity (92.3% for detecting CIN2/3, and 100% for CIN3), comparable to LA-HPV testing on cervical samples (96.0% and 100%, respectively), and higher than LA-HPV testing on urine samples (80.8% and 90.0%, respectively). In this referral population, the specificity of the Trovagene urine HPV test was non-significantly lower (29% for CIN2/3 and 25% for CIN3) than corresponding estimates of LA-HPV testing on cervical (36% and 28%, respectively) and urine (42% and 38%, respectively) samples. This pilot study suggests that the Trovagene HPV test has high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies.


Heavy metal tolerance in Stenotrophomonas maltophilia.
Stenotrophomonas maltophilia is an aerobic, non-fermentative Gram-negative bacterium widespread in the environment. S. maltophilia Sm777 exhibits innate resistance to multiple antimicrobial agents. Furthermore, this bacterium tolerates high levels (0.1 to 50 mM) of various toxic metals, such as Cd, Pb, Co, Zn, Hg, Ag, selenite, tellurite and uranyl. S. maltophilia Sm777 was able to grow in the presence of 50 mM selenite and 25 mM tellurite and to reduce them to elemental selenium (Se(0)) and tellurium (Te(0)) respectively. Transmission electron microscopy and energy dispersive X-ray analysis showed cytoplasmic nanometer-sized electron-dense Se(0) granules and Te(0) crystals. Moreover, this bacterium can withstand up to 2 mM CdCl(2) and accumulate this metal up to 4% of its biomass. The analysis of soluble thiols in response to ten different metals showed eightfold increase of the intracellular pool of cysteine only in response to cadmium. Measurements by Cd K-edge EXAFS spectroscopy indicated the formation of Cd-S clusters in strain Sm777. Cysteine is likely to be involved in Cd tolerance and in CdS-clusters formation. Our data suggest that besides high tolerance to antibiotics by efflux mechanisms, S. maltophilia Sm777 has developed at least two different mechanisms to overcome metal toxicity, reduction of oxyanions to non-toxic elemental ions and detoxification of Cd into CdS.


Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections.
Poxviruses continue to pose a major threat to human health. Monkeypox is endemic in central Africa, and the discontinuation of the vaccination (with vaccinia virus) has rendered most humans vulnerable to variola virus, the etiologic agent of smallpox, should this virus be used in biological warfare or terrorism. However, a large variety of compounds have been described that are potent inhibitors of vaccinia virus replication and could be expected to be active against other poxviruses as well. These compounds could be grouped in different classes: (i) IMP dehydrogenase inhibitors (e.g., EICAR); (ii) SAH hydrolase inhibitors (e.g., 5'-noraristeromycin, 3-deazaneplanocin A, and various neplanocin A derivatives); (iii) OMP decarboxylase inhibitors (e.g., pyrazofurin) and CTP synthetase inhibitors (e.g., cyclopentenyl cytosine); (iv) thymidylate synthase inhibitors (e.g., 5-substituted 2'-deoxyuridines); (v) nucleoside analogues that are targeted at viral DNA synthesis (e.g., Ara-A); (vi) acyclic nucleoside phosphonates [e.g., (S)-HPMPA and (S)-HPMPC (cidofovir)]; and (vii) polyanionic substances (e.g., polyacrylic acid). All these compounds could be considered potential candidate drugs for the therapy and prophylaxis of poxvirus infections at large. Some of these compounds, in particular polyacrylic acid and cidofovir, were found to generate, on single-dose administration, a long-lasting protective efficacy against vaccinia virus infection in vivo. Cidofovir, which has been approved for the treatment of cytomegalovirus retinitis in immunocompromised patients, was also found to protect mice, again when given as a single dose, against a lethal aerosolized or intranasal cowpox virus challenge. In a biological warfare scenario, it would be advantageous to be able to use a single treatment for an individual exposed to an aerosolized poxvirus. Cidofovir thus holds great promise for treating human smallpox, monkeypox, and other poxvirus infections. Anecdotal experience points to the efficacy of cidofovir in the treatment of the poxvirus infections molluscum contagiosum and orf (ecthyma contagiosum) in immunosuppressed patients.


Structure-property relations in linear viscoelasticity of supramolecular hydrogels.
Extraordinary mechanical properties of supramolecular gels (fracture toughness, fatigue resistance, injectability and self-healing ability) are strongly affected by their viscoelastic response driven by rearrangement (association and dissociation) of physical bonds. The kinetics of rearrangement is traditionally studied in small-amplitude shear oscillatory tests by analyzing the effect of the frequency of oscillations ω on the storage G' and loss G'' moduli. Conventional Maxwell-type models describe observations rather poorly when the gels reveal a pronounced flattening of the graphs G''(ω) at high frequencies. A simple model is derived in linear viscoelasticity of supramolecular gels. Its advantage is that the model reproduces experimental data correctly, on the one hand, and involves only four material constants, on the other. Based on the analysis of experimental data on gels cross-linked by coiled-coil complexes, covalent and ionic bonds, phenylboronic acid-diol complexes and metal-ligand coordination bonds, the model is applied to develop structure-property relations that describe the influence of chemical structure of supramolecular gels (concentration of polymer chains and type and molar fraction of temporary bonds) and environmental conditions (temperature, pH and ionic strength of buffer solutions) on their viscoelastic response.


Low-pathogenicity avian influenza virus (H6N2) in chickens in California, 2000-02.
During 2000, 2001, and January 2002, avian influenza virus was isolated from chickens from 12 different locations in California. All the isolates were typed as H6N2 and determined to be of low pathogenicity for chickens. Nine of the isolates came from commercial layer flocks; one from a backyard flock; one from a mixed age flock, where ducks and squabs were also present; and one from a primary broiler breeder. Although a drop in egg production and increased mortality were among the disease signs reported in the layer flocks, the pathological changes observed in the early cases were primarily associated with mild respiratory infections. It was not until August 2001 that yolk peritonitis was observed; this has been a feature of all the remaining cases through 2001 and 2002. All the isolates clustered as a unique group separate from other influenza viruses based upon sequence data of the H6, neuraminidase (N2), and matrix (MA) genes, indicating a common ancestor for these three gene segments. However, sequencing of the nonstructural (NS) gene indicates introductions from two separate origins. With the first isolate CK/CA/431/00 as the index case, the N2, MA, and NS genes are more closely related to North American isolates, as is the NP gene of CK/CA/650/00. In contrast, the H6 gene is more closely related to a Eurasian influenza isolate. Comparison of amino acid sequences of the N2 and MA genes of these isolates with available type A influenza viruses identified two unique changes in the MA gene and nine in the N2 gene, as well as four progressive changes. These results are discussed in relation to available clinical and epidemiological data.


Effects of a vibratory device on pain from anesthetic injections.
A randomized block, split-mouth design was used to determine the effectiveness of a vibratory device with topical anesthetic compared to topical anesthetic only in reducing the pain experienced during an inferior alveolar nerve block. Twenty participants each received two inferior alveolar injections with a 5-minute interval between injections, one with topical anesthetic and one with topical anesthetic and a vibratory device. Each injection included a 2-minute application of topical anesthetic gel at the injection site. Local anesthetic was administered bilaterally using a 27-gauge needle with or without the vibratory device. Participants rated the pain they experienced after each injection by using a visual analog scale (VAS). A mean VAS score and standard deviation was determined per group. Data was analyzed with a paired t test (α = 0.05). The group receiving the vibratory device with topical anesthetic had a mean VAS score of 21.2 mm ± 18.6 mm, and the group receiving the topical anesthetic alone had a VAS score of 38.7 mm ± 23.3 mm. The use of the vibratory device and topical anesthetic significantly reduced the pain experienced during the administration of a local anesthetic injection compared with the use of topical anesthetic alone (P = 0.006).


Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation.
Canonical Wnt signaling has been implicated in various aspects of hematopoiesis. Its role is controversial due to different outcomes between various inducible Wnt-signaling loss-of-function models and also compared with gain-of-function systems. We therefore studied a mouse deficient for a Wnt gene that seemed to play a nonredundant role in hematopoiesis. Mice lacking Wnt3a die prenatally around embryonic day (E) 12.5, allowing fetal hematopoiesis to be studied using in vitro assays and transplantation into irradiated recipient mice. Here we show that Wnt3a deficiency leads to a reduction in the numbers of hematopoietic stem cells (HSCs) and progenitor cells in the fetal liver (FL) and to severely reduced reconstitution capacity as measured in secondary transplantation assays. This deficiency is irreversible and cannot be restored by transplantation into Wnt3a competent mice. The impaired long-term repopulation capacity of Wnt3a(-/-) HSCs could not be explained by altered cell cycle or survival of primitive progenitors. Moreover, Wnt3a deficiency affected myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation. Our results show that Wnt3a signaling not only provides proliferative stimuli, such as for immature thymocytes, but also regulates cell fate decisions of HSC during hematopoiesis.


Changes in Vertebral Artery Blood Flow in Different Head Positions and Post-Cervical Manipulative Therapy.
The objective of this study was to investigate the hemodynamics of blood flow through the V3 region of the vertebral artery contralateral to the side manipulated during different rotary head positions and post-cervical spinal manipulation. This quasi-experimental study was performed on 25 healthy, asymptomatic participants, both male and female, between 20 and 30 years of age. Each participant presented with a C0/C1 or C1/C2 cervical facet restriction (as determined by motion palpation). Participation was voluntary, and participants had no symptoms of vertebrobasilar artery insufficiency or contraindications to cervical spinal manipulation. Doppler ultrasound was used to measure vertebral artery blood flow (V3 region) hemodynamics, contralateral side of manipulation, as close to C1/C2 region as possible in 4 positions of cervical rotation (neutral, 45°, maximum, and post-manipulation neutral). Doppler ultrasound parameters included peak systolic flow velocity, end diastolic flow velocity, mean flow velocity, vessel diameter, and flow rate. The nonparametric Friedman test was used for analysis across each head and neck position, and post manipulation. No clinical or statistically significant results (P > .05) were found for any of the hemodynamic parameters in any of the head positions. Hemodynamic measurements of the V3 region of the vertebral artery do not show significant changes in the measured head positions or following manipulation of the upper cervical spine in patients without pre-existing risk factors.


S-1 monotherapy versus S-1 combination therapy in gemcitabine-refractory advanced pancreatic cancer: A meta-analysis (PRISMA) of randomized control trials.
Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Most new cases are diagnosed based on metastasis or local aggression and are known as "advanced PC." Recently, studies investigating S-1 have indicated that it has a better clinical curative effect on PC. We conducted a meta-analysis to evaluate the efficacy and safety of S-1 monotherapy compared with S-1 combination regimens in patients with gemcitabine (GEM)-refractory PC. Trials published between 1978 and 2016 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library). All prospective studies were independently identified by 2 authors for inclusion. The response rate (RR), progression-free and overall survival (PFS and OS, respectively), and the primary toxicities were extracted for the meta-analysis. Four randomized controlled trials consisting of 623 patients were included in the analysis, among which 315 patients underwent S-1 monotherapy and 308 patients underwent S-1 combination therapy. The pooled data showed a significantly higher response rate and longer PFS in the S-1 combination group than in the S-1 monotherapy group (RR, 1.75; 95% confidence interval [CI], 1.19-2.57; P = .005 and hazard ration [HR], 0.75; 95% CI, 0.62-0.91; P = .005). There were no significant differences in OS or adverse events. Compared with the S-1 monotherapy group, the S-1 combination group had a higher response rate and longer PFS. Both groups had few adverse events, which were balanced between the groups. The subgroup analysis suggested that S-1 combination regimens with leucovorin or irinotecan (CPT-11) provided promising efficacy. These promising combination regimens should be considered for patients with advanced PC who choose S-1 as their second-line therapy.


Variability in the developmental life history of the genus Gorilla.
Life history is influenced by factors both intrinsic (e.g., body and relative brain size) and extrinsic (e.g., diet, environmental instability) to organisms. In this study, we examine the prediction that energetic risk influences the life history of gorillas. Recent comparisons suggest that the more frugivorous western lowland gorilla shows increased infant dependence, and thus a slower life history, than the primarily folivorous mountain gorilla to buffer against the risk of starvation during periods of food unpredictability. We further tested this hypothesis by incorporating additional life history data from wild western lowland gorillas and captive western lowland gorillas with the assumption that the latter live under ecological conditions of energetic risk that more closely resemble those of mountain gorillas and thus should show faster life histories than wild members of the species. Overall, we found captive western lowland and wild mountain gorillas to have faster developmental life histories than wild western lowland gorillas, weaning their infants approximately a year earlier and thus reducing interbirth intervals by a year. These results provide support that energetic risk plays an important role in determining gorilla life history. Unlike previous assertions, gorillas do not have substantially faster life histories, at least at the genus level, than other great apes. This calls for a re-evaluation of theories concerning comparative ape life history and evolution and highlights the need for data from additional populations that vary in energetic risk.


Deep vein and artery thrombosis associated with cetuximab-based chemoradiotherapy.
Molecular targeted agents have lower hematological toxicity. However, specific side-effects such as allergic rashes, skin reactions and high cost limit their use. We report a case of 35-year-old male patient with carcinoma of left tonsil treated with concurrent cetuximab and radiotherapy. After four weeks of treatment, the patient developed sudden onset of pain in the left calf region radiating to the left foot. Doppler study of the left lower limb revealed complete thrombosis of superficial femoral, popliteal and proximal tibial arteries and veins and no flow in anterior tibial artery and lower posterior tibial artery. Emergency embolectomy was done. After 48 h of observation, no improvement was noted. A repeat Doppler examination showed similar finding. Ultimately a left lower limb amputation was done. We report simultaneous arterio-venous thrombosis associated with cetuximab-based chemoradiotherapy. Oncologists should be aware of this possible complication to undertake early intervention.


[Use of lumbar puncture in the evaluation of late-onset sepsis in low birth weight neonates].
The objective of this study was to analyze the use of lumbar punctures (LP) in the evaluation of late-onset neonatal sepsis. It is recommended to perform an LP as part of the evaluation of late-onset sepsis. We used a cohort of 414 newborns with a birth weight <2000g in three hospitals in Lima. A LP was performed in 45/214 (21.0%) of sepsis evaluations and in 13/48 (27.1%) of culture-proven sepsis. Meningitis was diagnosed in 8/214 (3.7%) of the episodes and 8/45 (17.5%) of the evaluations that included an LP. The duration of treatment of the sepsis episodes without a LP and the episodes with a negative LP was similar, and shorter than the episodes with a positive LP. The use of LP in the evaluation of late-onset sepsis is low and can result in undiagnosed and undertreated meningitis. The use of LP in the evaluation of neonatal sepsis must be encouraged in the neonatal units.


Antivirals against enteroviruses: a critical review from a public-health perspective.
The enteroviruses (EVs) of the Picornaviridae family are the most common viral pathogens known. Most EV infections are mild and self-limiting but manifestations can be severe in children and immunodeficient individuals. Antiviral development is actively pursued to benefit these high-risk patients and, given the alarming problem of antimicrobial drug resistance, antiviral drug resistance is a public-health concern. Picornavirus antivirals can be used off-label or as part of outbreak control measures. They may be used in the final stages of poliovirus eradication and to mitigate EV-A71 outbreaks. We review the potential emergence of drug-resistant strains and their impact on EV transmission and endemic circulation. We include non-picornavirus antivirals that inhibit EV replication, for example, ribavirin, a treatment for infection with HCV, and amantadine, a treatment for influenza A. They may have spurred resistance emergence in HCV or influenza A patients who are unknowingly coinfected with EV. The public-health challenge is always to find a balance between individual benefit and the long-term health of the larger population.


New techniques and technology to repair cerebrospinal fluid rhinorrhea.
Cerebrospinal fluid rhinorrhea occurs as a result of abnormal communication between the subarachnoid space and the pneumatized portion of the skull base, the paranasal sinuses and the middle ear. Conservative measures may be sufficient in the management of cerebrospinal fluid rhinorrhea, but, in some cases, surgical treatment may be required. Transnasal endoscopic techniques are constantly being used in preference to the intra- and extracranial approaches. Recently, image guidance systems have been adopted in neurosurgery, skull base and paranasal sinus surgery. The present report refers to 4 cases of nasal cerebrospinal fluid rhinorrhea leak successfully treated with a transnasal endoscopic approach using various techniques and materials to close the bone defect, in 2 of which, the navigation system (Stealth Station Treon ENT Image Guidance System with Landmark X, Software, Medtronic, XOMED, Jacksonville, FL, USA) was also used. In all cases, correct localization and repair of the leak was achieved and no major complications occurred. Following a review of the literature, the Authors conclude that, at present, transnasal endoscopic repair of cerebrospinal fluid rhinorrhea is the surgical treatment of choice when the techniques and materials are correctly used. Furthermore, preliminary findings indicate that it is possible to make routine use of the navigation systems and that this technology may be usefully employed, above all, in the management of cerebrospinal fluid leaks.


Synthesis and field emission properties of different ZnO nanostructure arrays.
In this article, zinc oxide (ZnO) nanostructures of different shapes were fabricated on silicon substrate. Well-aligned and long ZnO nanowire (NW) arrays, as well as leaf-like ZnO nanostructures (which consist of modulated and single-phase structures), were fabricated by a chemical vapor deposition (CVD) method without the assistance of a catalyst. On the other hand, needle-like ZnO NW arrays were first fabricated with the CVD process followed by chemical etching of the NW arrays. The use of chemical etching provides a low-cost and convenient method of obtaining the needle-like arrays. In addition, the field emission properties of the different ZnO NW arrays were also investigated where some differences in the turn-on field and the field-enhancement factors were observed for the ZnO nanostructures of different lengths and shapes. It was experimentally observed that the leaf-like ZnO nanostructure is most suitable for field emission due to its lowest turn-on and threshold field as well as its high field-enhancement factor among the different synthesized nanostructures.


Role of endoscopic ultrasound and endoscopic retrograde cholangiopancreatography in isolated pancreatic metastasis from lung cancer.
A case is reported of a 50-year-old woman with a history of small-cell lung cancer admitted with pancreatic head lesions, discovered during investigation for obstructive jaundice. Endoscopic ultrasound assisted fine needle aspiration of the pancreatic mass was consistent with small cell carcinoma, presenting as an isolated metastasis from the previously diagnosed lung cancer. Endoscopic retrograde cholangiopancreatography (ERCP) showed extrinsic compression and a bile duct stricture, requiring sphincterotomy and stent insertion. This case highlights that acute pancreatitis and biliary obstruction can occur as a manifestation of small cell lung cancer metastasizing to the pancreas. EUS is a safe, low risk and rapid diagnostic tool in such cases, and ERCP with stenting offers a safe and effective treatment option.


The invariom model and its application: refinement of D,L-serine at different temperatures and resolution.
Three X-ray data sets of the same D,L-serine crystal were measured at temperatures of 298, 100 and 20 K. These data were then evaluated using invarioms and the Hansen & Coppens aspherical-atom model. Multipole populations for invarioms, which are pseudoatoms that remain approximately invariant in an intermolecular transfer, were theoretically predicted using different density functional theorem (DFT) basis sets. The invariom parameters were kept fixed and positional and thermal parameters were refined to compare the fitting against the multi-temperature data at different resolutions. The deconvolution of thermal motion and electron density with respect to data resolution was studied by application of the Hirshfeld test. Above a resolution of sin theta/lambda approximately 0.55 A-1, or d approximately 0.9 A, this test was fulfilled. When the Hirshfeld test is fulfilled, a successful modeling of the aspherical electron density with invarioms is achieved, which was proven by Fourier methods. Molecular geometry improves, especially for H atoms, when using the invariom method compared to the independent-atom model, as a comparison with neutron data shows. Based on this example, the general applicability of the invariom concept to organic molecules is proven and the aspherical density modeling of a larger biomacromolecule is within reach.


Towards industrial biological hydrogen production: a review.
Increased production of renewable energy sources is becoming increasingly needed. Amidst other strategies, one promising technology that could help achieve this goal is biological hydrogen production. This technology uses micro-organisms to convert organic matter into hydrogen gas, a clean and versatile fuel that can be used in a wide range of applications. While biohydrogen production is in its early stages, several challenges must be addressed for biological hydrogen production to become a viable commercial solution. From an experimental perspective, the need to improve the efficiency of hydrogen production, the optimization strategy of the microbial consortia, and the reduction in costs associated with the process is still required. From a scale-up perspective, novel strategies (such as modelling and experimental validation) need to be discussed to facilitate this hydrogen production process. Hence, this review considers hydrogen production, not within the framework of a particular production method or technique, but rather outlines the work (bioreactor modes and configurations, modelling, and techno-economic and life cycle assessment) that has been done in the field as a whole. This type of analysis allows for the abstraction of the biohydrogen production technology industrially, giving insights into novel applications, cross-pollination of separate lines of inquiry, and giving a reference point for researchers and industrial developers in the field of biohydrogen production.


Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE).
The potential role of oestrogenic agents, antioxidants and intestinal glucose-uptake inhibitors in the treatment of diabetes is briefly reviewed. Reports in the literature suggest that oestrogen replacement therapy may favourably modulate glucose homeostasis. A soya phytochemical extract (SPE) containing the isoflavone phytoestrogens genistein and daidzein (mostly in their glycone forms as genistin and daidzin) was investigated as an antioxidant and modulator of intestinal glucose-transport. In the present study, SPE was found to protect against glucose-induced oxidation of human low density lipoproteins (LDL) in vitro. Equol (a gut bacterial metabolite of daidzein) was a more effective antioxidant than daidzein or genistein in this system and was of similar antioxidant potency to the dietary flavonols quercetin and kaempferol and to the endogenous antioxidant 17beta-oestradiol. SPE was found to be an inhibitor of glucose uptake into rabbit intestinal brush border membrane vesicles in vitro, though of weaker potency than the classical sodium dependent glucose transporter (SGLT) inhibitor, phlorizin. Thus SPE displays a range of properties which may be of benefit in diabetes, namely as an oestrogenic agent, an inhibitor of intestinal glucose-uptake and a preventive agent for glucose-induced lipid peroxidation.


Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma.
Histone acetylation status is a key factor in the regulation of inflammatory gene transcription. We investigated the activity of histone acetylases (HAT) and deacetylases (HDAC), and the effect of glucocorticoids in alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) from subjects with asthma. Bronchoalveolar lavage was performed in 10 patients with intermittent asthma, 8 with persistent asthma, and 10 healthy control subjects. PBMCs and granulocytes were isolated from six patients with mild and severe asthma, before and after a 7-day course of prednisolone (30 mg/day). AMs were isolated for HDAC assay or incubated with dexamethasone (1 microM). HAT activity was increased (1.43 +/- 0.1 vs. 1.01 +/- 0.1 standard units/10 microg, p < 0.05), and HDAC activity was reduced (3031 +/- 243 vs. 5004 +/- 164 arbitrary fluorescence units/10 microg, p < 0.001) in AMs of subjects with asthma compared with control subjects. Dexamethasone suppressed LPS-induced granulocyte macrophage-colony stimulating factor, tumor necrosis factor-alpha, and interleukin-8 release by 83 +/- 1%, 51 +/- 7% and 20 +/- 9% (p < 0.001), respectively. Similar effects were seen on nuclear factor-kappaB inhibition, and interleukin-8 release was further reduced by the HDAC enhancer, theophylline (37 +/- 6%). Prednisolone increased HDAC activity in PBMCs from subjects with mild asthma. The increased inflammatory response in asthma may be due to reduced HDAC and enhanced HAT activity. Glucocorticoids and theophylline may downregulate the inflammatory response by modulating HAT and HDAC activity, and nuclear factor-kappaB activation.


Clinically important improvement in function is common in people with or at high risk of knee OA: the MOST study.
To calculate the frequency of clinically important improvement in function over 30 months and identify risk factors in people who have or are at risk of knee osteoarthritis (OA). Subjects were from the Multicenter Osteoarthritis (MOST), a longitudinal study of persons with or at high risk of knee OA. We defined minimal clinically important improvement (MCII) with the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) physical function using 3 different methods. Baseline risk factors tested for improvement included age, sex, educational attainment, presence of radiographic knee OA (ROA), the number of comorbidities, body mass index (BMI), knee pain, walking speed, isokinetic knee extensor strength, depressive symptoms, physical activity, and medication usage. We used logistic regression to evaluate the association of baseline risk factors with MCII. Of the 1801 subjects (mean age 63 yrs, BMI = 31, 63% women), most had mild limitations in baseline function (WOMAC = 19 +/- 11). Regardless of how defined, a substantial percentage of subjects (24%-39%) reached MCII at 30 months. Compared to their counterparts, people with MCII were less likely to have ROA and to use medications, and were more likely to have a lower BMI, less knee pain, a faster walking speed, more knee strength, and fewer depressive symptoms. After adjustment, MCII was 40% to 50% less likely in those with ROA, and 1.9 to 2.0 times more likely in those walking 1.0 meters/second faster than counterparts. Clinically important improvement is frequent in people with or at high risk of knee OA. The absence of ROA and a faster walking speed appear to be associated with clinically important improvements.


Inhibition of HIV-1 ribonuclease H activity by novel frangula-emodine derivatives.
The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT polymerase and integrase activities in biochemical assays. Given the structural similarities between integrase and RNase H proteins, we synthesized a series of frangula-emodine derivatives and showed that the introduction of a bromine atom in position 7 of the anthraquinone structure leads to derivatives which are able to inhibit both HIV-1 polymerase and RNase H functions at micromolar concentrations. Mechanism of action studies performed on the 7-brom-6-capital O, Cyrillic-phenacyl-1,8-dihydroxy-3-methyl anthraquinone (K67) showed that this compound is a non-competitive inhibitor of the RNase H function and that it binds to a site which is not overlapping to the non-nucleoside RT inhibitors binding site. This study demonstrates that anthraquinone derivatives may be a scaffold to be further developed to obtain selective HIV-1 RNase H inhibitors and represent a new step toward the identification of new anti-RT agents.


Incidence, predictors, and etiology of subsequent ischemic stroke within one year after transient ischemic attack.
Background Incidence and predictors of ischemic stroke in patients with transient ischemic attack (TIA) have not been fully clarified outside Europe and North America. Aims We undertook the present prospective, multicenter study to clarify the incidence, predictors, and etiology of ischemic stroke within one year of TIA onset in Japan. Methods The study subjects were patients within seven days of TIA onset who were enrolled in a prospective register from 57 hospitals between June 2011 and December 2013. The primary endpoint was occurrence of ischemic stroke. Results Of 1365 consecutive patients, 1245 were followed for one year after TIA onset; 101 (8.1%) experienced ischemic stroke during follow-up. The leading subtype of ischemic stroke was small-vessel occlusion (SVO) followed by large-artery atherosclerosis (LAA) attributable to intracranial artery diseases. When dividing ischemic stroke events between those occurring within the first 90 days after TIA onset and those occurring after the first 90 days, the leading subtype of ischemic stroke within the first 90 days after TIA onset was SVO, followed by LAA attributable to intracranial artery diseases. In comparison, the subtypes most commonly seen beyond the first 90 days after TIA onset were cardioembolic and LAA attributable to intracranial artery disease. The one-year risk of ischemic stroke increased significantly as ABCD2 score increased, at 6.2% for 0-3 points, 7.2% for 4-5 points, and 11.6% for 6-7 points. Conclusions The one-year ischemic stroke risk after TIA was about 8% and was associated with the ABCD2 score. The most common subtype of subsequent ischemic stroke was SVO.


Side-to-side arteriovenous fistula at the elbow with perforating vein ligation.
We postulated that ligation of a consistent perforating venous branch at the elbow would improve distention and flow in the superficial veins about the elbow. This would also lesson the likelihood of arterial steal enabling a favorable outcome following a brachial artery medial antecubital or cephalic vein arterio-venous fistula (AVF). Pressure measurements were made from the radial artery after side-to-side brachial artery antecubital or cephalic vein AVF in 20 patients. Clamping of the perforating vein increased radial artery pressure significantly indicating that a considerable amount of flow from the side-to-side AVF was diverted into the deep system and away from the accessible superficial veins. Encouraged by this finding, we studied the outcome of brachial cephalic or brachial antecubital AVF with ligation of the deep branch in 134 patients who were not candidates for radio-cephalic AVF. The end point of the study was successful hemodialysis using the fistula. Of the 134 patients treated, 24 died, and 11 were lost to follow-up and were censored from analysis of fistula performance at that time point. The primary fistula success rate was 89.7% +/- 2.66% and 83.7% +/- 3.5% at 1 and 2 years by life table analysis. No patient developed significant arterial steal or venous hypertension. We recommend this simple one-stage procedure for patients requiring hemodialysis whose cephalic vein at the wrist is unsuitable.