Characteristics of Pediatric Performance on a Test Battery Commonly Used in the Diagnosis of Central Auditory Processing Disorder.
Although central auditory processing disorder (CAPD) test battery performance has been examined in adults with neurologic lesions of the central auditory nervous system (CANS), similar data on children being referred for CAPD evaluations are sparse. This study characterizes CAPD test battery performance in children using tests commonly administered to diagnose the disorder. Specifically, this study describes failure rates for various test combinations, relationships between CAPD tests used in the battery, and the influence of cognitive function on CAPD test performance and CAPD diagnosis. A comparison is also made between the performance of children with CAPD and data from patients with neurologic lesions of the CANS. A retrospective study. Fifty-six pediatric patients were referred for CAPD testing. Participants were administered four CAPD tests, including frequency patterns (FP), low-pass filtered speech (LPFS), dichotic digits (DD), and competing sentences (CS). In addition, they were given the Wechsler Intelligence Scale for Children (WISC). Descriptive analyses examined the failure rates of various test combinations, as well as how often children with CAPD failed certain combinations when compared with adults with CANS lesions. A principal components analysis was performed to examine interrelationships between tests. Correlations and regressions were conducted to determine the relationship between CAPD test performance and the WISC. Results showed that the FP and LPFS tests were most commonly failed by children with CAPD. Two-test combinations that included one or both of these two tests and excluded DD tended to be failed more often. Including the DD and CS test in a battery benefited specificity. Tests thought to measure interhemispheric transfer tended to be correlated. Compared with adult patients with neurologic lesions, children with CAPD tended to fail LPFS more frequently and DD less frequently. Both groups failed FP with relatively equal frequency. The two-test combination that showed the highest failure rate for children with CAPD was LPFS-FP. Comparison with adults with CANS lesions, however, suggests that the mechanisms underlying LPFS performance in children need to be better understood. The two-test combination that showed the next highest failure rates among children with CAPD and did not include LPFS was CS-FP. If it is desirable to use a dichotic measure that has a lower linguistic load than CS then DD can be substituted for CS despite the slightly lower failure rate of the DD-FP battery.


Bronchial reactivity to cigarette smoke in smokers: repeatability, relationship to methacholine reactivity, smoking and atopy.
Bronchial reactivity to cigarette smoke (CBR) in a cross-section of 98 smokers has been investigated. All participants were subjects to skin-prick tests to common allergens, lung function measurements and bronchial challenges with methacholine and cigarette smoke. In 38 participants a rechallenge with cigarettes was performed 1 h after the first cigarette challenge. Lung function indices analysed were: forced expiratory volume in one second (FEV1); maximal expiratory flow at 75% of the forced vital capacity (MEF75%); and forced mid-expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75%)). All participants were tested for asthma and allergy, and were required to provide information regarding respiratory symptoms, first degree relatives with asthma and allergy and smoking habits. A substantial decrease was seen in all lung function indices after 12 cigarette-smoke inhalations, but only FEV1 was related to other variables. The maximal mean percentage fall in FEV1 was 10%, which was directly related to the number of inhalations (p<0.05). In multiple regression analyses the percentage fall in FEV1 was directly related to: FEV1/vital capacity (VC) (p<0.01); to the asthmatic/bronchitic status (p<0.05); and to the accumulated and standardized cigarette consumption (p<0.05). The percentage fall in FEV1 bore no relationship to methacholine bronchial reactivity, sex or age and had a continuous distribution. The repeat challenge showed a smaller fall in FEV1 compared to the first challenge after 12 cigarette smoke inhalations (p<0.05). The percentage fall in FEV1 correlated after the first and the repeat challenge (p<0.05). Repeatability of the challenge could not be determined in this study because of tachyphylaxis. Bronchial reactivity to cigarette smoke is a tobacco smoke-specific bronchial response. All participants responded and the response showed a continuous distribution. Bronchial reactivity to cigarette smoke may be of importance for symptoms and prognosis in chronic bronchitis and chronic obstructive pulmonary disease and should be studied in relation to the degree of accelerated lung function loss in smokers and other cigarette induced lung abnormalities.


Age-period-cohort analysis of Swiss suicide data, 1881-2000.
At the end of the 19(th) century, male suicide rates in Switzerland were as high as the respective rates in recent decades, whereas female suicide rates were distinctly lower. An age-period-cohort analysis was performed to provide more information about the gender-specific changes over the last century. Suicide mortality has been reported in Switzerland since 1876 when the standardised registration of mortality data began. The analysed data cover the period 1881-2000. The statistical analyses were based on log-linear models and data aggregated by 10-year age-intervals and 10-year period intervals. The results indicate similar age and period effects in males and females. The estimates representing age-specific risk increase steadily with age, with intermediate plateaus in the 20s and the 50s. The period-specific estimates follow the economic cycles. The birth cohort effects are stronger in males and weaker in females. In the males' estimates, there is a peak in cohorts born around 1840 and a low in cohorts born some 60-100 years later. The estimates increased again in generations born after World War II. In females, the birth cohort estimates are low in cohorts born in the first half of the 19(th) century and increase until the first half of the 20(th) century. Birth cohort effects remain an intriguing topic in epidemiology of suicide. A better understanding of birth cohort effects might open new doors to suicide prevention.


Neurocognitive patterns across genetic levels in behavioral variant frontotemporal dementia: a multiple single cases study.
Behavioral variant frontotemporal dementia (bvFTD) has been related to different genetic factors. Identifying multimodal phenotypic heterogeneity triggered by various genetic influences is critical for improving diagnosis, prognosis, and treatments. However, the specific impact of different genetic levels (mutations vs. risk variants vs. sporadic presentations) on clinical and neurocognitive phenotypes is not entirely understood, specially in patites from underrepresented regions such as Colombia. Here, in a multiple single cases study, we provide systematic comparisons regarding cognitive, neuropsychiatric, brain atrophy, and gene expression-atrophy overlap in a novel cohort of FTD patients (n = 42) from Colombia with different genetic levels, including patients with known genetic influences (G-FTD) such as those with genetic mutations (GR1) in particular genes (MAPT, TARDBP, and TREM2); patients with risk variants (GR2) in genes associated with FTD (tau Haplotypes H1 and H2 and APOE variants including ε2, ε3, ε4); and sporadic FTD patients (S-FTD (GR3)). We found that patients from GR1 and GR2 exhibited earlier disease onset, pervasive cognitive impairments (cognitive screening, executive functioning, ToM), and increased brain atrophy (prefrontal areas, cingulated cortices, basal ganglia, and inferior temporal gyrus) than S-FTD patients (GR3). No differences in disease duration were observed across groups. Additionally, significant neuropsychiatric symptoms were observed in the GR1. The GR1 also presented more clinical and neurocognitive compromise than GR2 patients; these groups, however, did not display differences in disease onset or duration. APOE and tau patients showed more neuropsychiatric symptoms and primary atrophy in parietal and temporal cortices than GR1 patients. The gene-atrophy overlap analysis revealed atrophy in regions with specific genetic overexpression in all G-FTD patients. A differential family presentation did not explain the results. Our results support the existence of genetic levels affecting the clinical, neurocognitive, and, to a lesser extent, neuropsychiatric presentation of bvFTD in the present underrepresented sample. These results support tailored assessments characterization based on the parallels of genetic levels and neurocognitive profiles in bvFTD.


Effect of retroviral proteinase inhibitors on Mason-Pfizer monkey virus maturation and transmembrane glycoprotein cleavage.
Mason-Pfizer monkey virus (M-PMV) is the prototype type D retrovirus which preassembles immature intracytoplasmic type A particles within the infected cell cytoplasm. Intracytoplasmic type A particles are composed of uncleaved polyprotein precursors which upon release are cleaved by the viral proteinase to their constituent mature proteins. This results in a morphological change in the virion described as maturation. We have investigated the role of the viral proteinase in virus maturation and infectivity by inhibiting the function of the enzyme through mutagenesis of the proteinase gene and by using peptide inhibitors originally designed to block human immunodeficiency virus type 1 proteinase activity. Mutation of the active-site aspartic acid, Asp-26, to asparagine abrogated the activity of the M-PMV proteinase but did not affect the assembly of noninfectious, immature virus particles. In mutant virions, the transmembrane glycoprotein (TM) of M-PMV, initially synthesized as a cell-associated gp22, is not cleaved to gp20, as is observed with wild-type virions. This demonstrates that the viral proteinase is responsible for this cleavage event. Hydroxyethylene isostere human immunodeficiency virus type 1 proteinase inhibitors were shown to block M-PMV proteinase cleavage of the TM glycoprotein and Gag-containing precursors in a dose-dependent manner. The TM cleavage event was more sensitive than cleavage of the Gag precursors to inhibition. The infectivity of treated particles was reduced significantly, but experiments showed that inhibition of precursor and TM cleavage may be at least partially reversible. These results demonstrate that the M-PMV aspartyl proteinase is activated in released virions and that the hydroxyethylene isostere proteinase inhibitors used in this study exhibit a broad spectrum of antiretroviral activity.


Low-Lying Electronic States of CuAu.
Coinage metal diatomic molecules are building blocks for nanostructured materials, electronic devices, and catalytically or photochemically active systems that are currently receiving lively interest in both fundamental and applied research. The theoretical study presented here elucidates the electronic structure in the ground and several low-lying excited states of the diatomic molecule CuAu that result from the combination of the atoms in their ground states nd(10)(n + 1)s(1 2)S and lowest excited d-hole states nd(9)(n + 1)s(2 2)D (n = 3 for Cu, n = 5 for Au). Full and smooth potential energy curves, obtained at the multireference configuration interaction (MRCI) level of theory, are presented for the complete set of the thus resulting 44 Λ-S terms and 86 Ω terms. Our approach is based on a scalar relativistic description using the Douglas-Kroll-Hess (DKH) Hamiltonian, with subsequent perturbative inclusion of spin-orbit (SO) coupling via the spin-orbit terms of the Breit-Pauli (BP) Hamiltonian. The Ω terms span an energy interval of about 7 eV at the ground state's equilibrium distance. Spectroscopic constants, calculated for all terms, are shown to accurately reproduce the observation for those nine terms that are experimentally known.


A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer.
Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.


Telmisartan in daily clinical practice: factors affecting efficacy in treatment of primary arterial hypertension.
Telmisartan provides effective treatment of hypertension in a broad spectrum of patients. To evaluate factors affecting the efficacy of telmisartan in daily clinical practice. Prospective practice-based 12-week uncontrolled cohort study. Consecutive incident/prevalent outpatients with mild to moderate essential hypertension were started on telmisartan 40 mg/day with optional up-titration to 80 mg/day in order to achieve seated systolic (SSBP) and diastolic (SDBP) blood pressure < 140/90 mm Hg. Intent-to-treat (ITT, N=282) and per protocol (PP, N=275) efficacy assessment was based on SSBP/SDBP reduction and delivered doses. SSBP/SDBP decreased (165.2+/-13.1 / 98.3+/-6.7 mm Hg to 137.9+/-13.2 / 82.6+/-7.3 mm Hg), whilst telmisartan was up-titrated in 40.5% of patients during the study. Multivariate (practically identical ITT and PP) analysis indicated poorer response in obese vs. non-obese patients: lesser SDBP reduction (by around 2.2-2.3 mm Hg, P < 0.05) with higher odds of dose up-titration (odds ratio, OR around 1.90, P < 0.05); and better response in: a) patients started on telmisartan monotherapy than when added to a preexisting treatment: greater SSBP/SDBP reduction (by around 4.0 and 3.0 mm Hg, respectively, P < 0.05) with comparable odds of up-titration; b) diabetics vs. non-diabetics: greater SDBP reduction (by around 3.6-3.7 mm Hg, P < 0.05) with comparable odds of up-titration; c) men vs. women: slightly greater SDBP reduction (by around 1.2 mm Hg, 0.05 P < 0.1) with lower odds of up-titration (OR around 0.51, P < 0.05). Previous unsuccessful treatment, obesity, diabetes and gender should be considered in order to optimize the use of telmisartan for mild to moderate essential hypertension in daily clinical practice.


Mechanism Exploration of Ion Transport in Nanocomposite Cation Exchange Membranes.
The origin of property enhancement of nanocomposite ion exchange membranes (IEMs) is far from being fully understood. By combining experimental work and computational modeling analysis, we could determine the influence of nanomaterials on the ion transport properties of nanocomposite cation exchange membranes (CEMs). We synthesized and characterized a series of nanocomposite CEMs by using SPPO as polymer materials and silica nanoparticles (NPs) (unsulfonated or sulfonated) as nanomaterials. We found that with the increase of NP loading, measured CEM permselectivity and swelling degree first increased and then decreased. We also found the ion exchange capacity (IEC) and ionic resistance of nanocomposite CEMs tend to be the same, regardless what type of NPs are incorporated into the membrane. Modeling analysis suggests that the change of membrane properties is related to the change in membrane microstructure. With the addition of silica NPs, membrane porosity (volume fraction of intergel phase) increases so that membranes can absorb more water. Also, volume fraction of sulfonated polymer segments increases, which can allow membranes to retain more counterions, causing membrane IEC to increase. By calculating the effective ion diffusion coefficients and membrane tortuosity factors of all the silica-NP-based CEMs synthesized in this study, along with nanocomposite CEMs from previous studies, we conclude that membrane ion transport efficiency tends to increase with the incorporation of nanomaterials. In addition, this paper presents a simulation model, which explains how the membrane property changes upon nanomaterial aggregation; the simulation results are in good agreement with the experimental data. Simulation results indicate that membrane properties are related to nanomaterial number concentration in the membrane matrices; thus, a plateau is reached for membrane ion diffusion coefficients due to the severe influence of aggregation on the increase of nanomaterial real number concentration. The results of this study can provide insight into membrane structure-property relation and contribute to the value of future designs of new nanocomposite IEMs.


Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count.
The optimal treatment for patients with autoimmune thrombocytopenic purpura (AITP) and a platelet count < or =20x10(9)/L is intravenous immunoglobulin (IVIg) but this treatment is expensive and steroids are a good alternative in less severe cases. Since the occurrence of life-threatening hemorrhage in adult AITP is a rare event, the aim of our study was to validate a therapeutic strategy based on a bleeding score for the short-term management of adults with AITP and a platelet count < or =20x10(9)/L. We developed a method to quantify hemorrhage in adults with AITP. Bleeding severity was graded on a numerical scale based on physical examination. When the bleeding score was < or =8, the patients were treated with steroids alone. For scores >8, patients received IVIg (1 to 2 g/kg) in combination with oral steroids. A good response was defined as the lowering of the initial bleeding score within 2 days after treatment initiation regardless of the platelet count. We applied this strategy for the management of 60 consecutive adults (mean age 48+/-23 years) with AITP and a platelet count < or =20x10(9)/L/L (mean platelet count 6+/-5x10(9)/L/L). Based on this strategy, IVIg was required in only 50% of the patients and no life-threatening bleeding occurred in patients treated with steroids alone. A therapeutic strategy based on a bleeding score rather than the platelet count appears to be relevant and safe and is a good IVIg-sparing strategy.


Bone densitometry at a district general hospital: evaluation of service by doctors and patients.
To assess doctors' and patients' views about a district general hospital bone densitometry service and to examine existing practice to influence future provision. Three postal surveys: (a) of doctors potentially using the service, (b) of patients undergoing a bone densitometry test during a six month period, and (c) of the referring doctors of the patients undergoing the test. Bone densitometry service at South Cleveland Hospital, Middlesbrough and two district health authorities: South Tees and Northallerton. All general practitioners (n=201) and hospital consultants in general medicine, rheumatology, obstetrics and gynaecology, orthopaedics, radio therapy and oncology, haematology, and radiology (n=61); all patients undergoing an initial bone densitometry test (n=309) during a six month period; and their referring doctors. Service awareness and use, knowledge of clinical indications, test results, influence of test results on patient management, satisfaction with the service and its future provision. The overall response rates for the three surveys were 87%, 70%, and 61%. There was a high awareness of the service among doctors and patients; 219(84%) doctors were aware and 155 of them (71%) had used it, and patients often (40%) suggested the test to their doctor. The test was used for a range of reasons including screening although the general use was consistent with current guidelines. Two hundred (65%) bone densitometry measurements were normal, 71(23%) were low normal, and 38(12%) were low. Although doctors reported that management of patients had been influenced by the test results, the algorithm for decision making was unclear. Patients and doctors were satisfied with the service and most (n=146, 68%) doctors wanted referral guidelines for the service. There was a high awareness of, use of, and satisfaction with the service. Patients were being referred for a range of reasons and a few of these could not be justified, many tests were normal, and clinical decision making was not always influenced by the test result. It is concluded that bone densitometry services should be provided but only for patients whose management will be influenced by test results and subject to guidelines to ensure appropriate use of the technology.


Apraxia of speech and cerebellar mutism syndrome: a case report.
Cerebellar mutism syndrome (CMS) or posterior fossa syndrome (PFS) consists of a constellation of neuropsychiatric, neuropsychological and neurogenic speech and language deficits. It is most commonly observed in children after posterior fossa tumor surgery. The most prominent feature of CMS is mutism, which generally starts after a few days after the operation, has a limited duration and is typically followed by motor speech deficits. However, the core speech disorder subserving CMS is still unclear. This study investigates the speech and language symptoms following posterior fossa medulloblastoma surgery in a 12-year-old right-handed boy. An extensive battery of formal speech (DIAS = Diagnostic Instrument Apraxia of Speech) and language tests were administered during a follow-up of 6 weeks after surgery. Although the neurological and neuropsychological (affective, cognitive) symptoms of this patient are consistent with Schmahmann's syndrome, the speech and language symptoms were markedly different from what is typically described in the literature. In-depth analyses of speech production revealed features consistent with a diagnosis of apraxia of speech (AoS) while ataxic dysarthria was completely absent. In addition, language assessments showed genuine aphasic deficits as reflected by distorted language production and perception, wordfinding difficulties, grammatical disturbances and verbal fluency deficits. To the best of our knowledge this case might be the first example that clearly demonstrates that a higher level motor planning disorder (apraxia) may be the origin of disrupted speech in CMS. In addition, identification of non-motor linguistic disturbances during follow-up add to the view that the cerebellum not only plays a crucial role in the planning and execution of speech but also in linguistic processing. Whether the cerebellum has a direct or indirect role in motor speech planning needs to be further investigated.


Engineering carbon nanotubes and nanotube circuits using electrical breakdown.
Carbon nanotubes display either metallic or semiconducting properties. Both large, multiwalled nanotubes (MWNTs), with many concentric carbon shells, and bundles or "ropes" of aligned single-walled nanotubes (SWNTs), are complex composite conductors that incorporate many weakly coupled nanotubes that each have a different electronic structure. Here we demonstrate a simple and reliable method for selectively removing single carbon shells from MWNTs and SWNT ropes to tailor the properties of these composite nanotubes. We can remove shells of MWNTs stepwise and individually characterize the different shells. By choosing among the shells, we can convert a MWNT into either a metallic or a semiconducting conductor, as well as directly address the issue of multiple-shell transport. With SWNT ropes, similar selectivity allows us to generate entire arrays of nanoscale field-effect transistors based solely on the fraction of semiconducting SWNTs.


Late gastrointestinal toxicities following radiation therapy for prostate cancer.
Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse. To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1-T2 prostate cancer. We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks. GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis. Among 41,737 patients in this study, 28,088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97-5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06-4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients. Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr.


Adaptive Structure Concept Factorization for Multiview Clustering.
Most existing multiview clustering methods require that graph matrices in different views are computed beforehand and that each graph is obtained independently. However, this requirement ignores the correlation between multiple views. In this letter, we tackle the problem of multiview clustering by jointly optimizing the graph matrix to make full use of the data correlation between views. With the interview correlation, a concept factorization-based multiview clustering method is developed for data integration, and the adaptive method correlates the affinity weights of all views. This method differs from nonnegative matrix factorization-based clustering methods in that it can be applicable to data sets containing negative values. Experiments are conducted to demonstrate the effectiveness of the proposed method in comparison with state-of-the-art approaches in terms of accuracy, normalized mutual information, and purity.


[Use of body mass index to evaluate the nutritional status of Xavánte Indigenous adults, Sangradouro-Volta Grande, Mato Grosso State, Central Brazil].
This study evaluates the relationship between Body Mass Index (BMI) and anthropometric measurements in Xavánte adults on the Sangradouro-Volta Grande Indian Reservation, Mato Grosso State, Central Brazil. The objective was to analyze the use of BMI as an indicator of nutritional status in this specific population. Fieldwork was conducted in January-February 1999. Data include body mass, height, arm, hip, and waist circumference, and triceps skinfold of 128 adults over 20 years of age. The results indicate high correlations (r > 0.80) between BMI and body mass and waist and mid upper arm circumference for both sexes. For women, fat arm area and total arm area were also highly correlated with BMI, while for men hip circumference and total arm area showed a high correlation with BMI. The results suggest that high BMI values are related to excess fat among the Xavánte. It is important to monitor changes in the nutritional status of indigenous peoples in Brazil, since there is evidence that such populations are undergoing rapid processes of nutritional transition.


Physiotherapists as detectives: investigating clues and plots in the clinical encounter.
This article investigates the clinical reasoning process of physiotherapists working with patients with chronic muscle pain. The article demonstrates how physiotherapists work with clues and weigh up different plots as they seek to build consistent stories about their patient's illness. The material consists of interviews with 10 Norwegian physiotherapists performed after the first clinical encounter with a patient. Using a narrative approach and Lonergan's theory of interpretation, the study highlights how, like detectives, the therapists work with clues by asking a number of interpretive questions of their data. They interrogate what they have observed and heard during the first session, they also question how the patient's story was told, including the contextual and relation aspects of clue production, and they ask why the patient's story was told to them in this particular way at this particular time. The article shows how the therapists configure clues into various plots on the basis of their experience of working with similar cases and how their detective work is pushed forward by uncertainty and persistent questioning of the data.


Psychopathology, childhood sexual abuse and other childhood adversities: relative links to subsequent suicidal behaviour in the US.
Research shows that psychopathology, child sexual abuse and other childhood adversities are risk factors for suicide. However, few have investigated their joint and independent roles in the pursuit of a reliable, predictive model of suicidal behaviour. Data are from the National Comorbidity Survey (N = 5877), a nationally representative study of prevalence, risk factors, and social consequences of psychiatric disorders in the US. Discrete time survival analysis and population attributable risk methodologies were utilized. Among those sexually abused as children, odds of suicide attempts were 2-4 times higher among women and 4-11 times higher among men, compared with those not abused, controlling for other adversities. Odds ratios were reduced but most remained statistically significant after adjusting for lifetime psychiatric illnesses preceding suicide attempts. In the same predictive equation, 79% of serious suicide attempts among women could be attributed to psychiatric disorders while 12% was attributable to rape and 7% to molestation. The highest probability of a first attempt was during early adolescence for those who were sexually abused and had a lifetime disorder, but it was 8-12 years older for those sexually abused without any disorders. In the US, a strong association exists between child sexual abuse and suicidal behaviour, mediated by psychopathology. There is a substantial proportion of suicide risk attributable to child sexual abuse beyond the presence of psychopathology and other adversities. From a clinical standpoint, abuse survivors represent a high-risk population for suicidal behaviour. Further research into this preventable antecedent of suicide attempts is necessary.


The influence of baroreflex sensitivity on ambulatory arterial stiffness index in individuals with cardiovascular risk.
Although the predictor role of ambulatory arterial stiffness index (AASI) for cardiovascular risk has been shown, the question of whether AASI is a measure of arterial stiffness or, in fact, reflects influence of other origins on the arterial tree remains to be determined. We sought to elucidate whether AASI is associated with baroreflex sensitivity (BRS) or blood pressure (BP) reactivity to stress in individuals with cardiovascular risk. A total of 120 participants were included in this study. Ambulatory BP measurements were performed over a 24-h period. AASI was calculated as 1 minus the regression slope of diastolic on systolic BP obtained from 24-h ambulatory BP monitoring data. BRS was estimated from the spontaneous changes in systolic BP and corresponding interbeat heart rate intervals. BP reactivity was induced by three stressors including the Stroop Color and Word Test, anger recall interview, and handgrip exercise. Arterial stiffness was determined by the pulse wave velocity. AASI significantly and inversely correlated to resting BRS (r=-0.24, P=0.01) and BRS under stress (r=-0.33, P=0.02) but not with systolic blood pressure reactivity (P=0.92) or pulse wave velocity (P=0.53). Adjusting for possible confounders, BRS independently predicted AASI (P=0.01). Increased AASI is associated with reduced BRS. Decreased BRS may at least in part explain the prognostic role of AASI in predicting cardiovascular risk. Our findings add support to the clinical significance of AASI. In particular, AASI may aid in the detection of cardiovascular risk.


Response process and test-retest reliability of the Context Assessment for Community Health tool in Vietnam.
The recently developed Context Assessment for Community Health (COACH) tool aims to measure aspects of the local healthcare context perceived to influence knowledge translation in low- and middle-income countries. The tool measures eight dimensions (organizational resources, community engagement, monitoring services for action, sources of knowledge, commitment to work, work culture, leadership, and informal payment) through 49 items. The study aimed to explore the understanding and stability of the COACH tool among health providers in Vietnam. To investigate the response process, think-aloud interviews were undertaken with five community health workers, six nurses and midwives, and five physicians. Identified problems were classified according to Conrad and Blair's taxonomy and grouped according to an estimation of the magnitude of the problem's effect on the response data. Further, the stability of the tool was examined using a test-retest survey among 77 respondents. The reliability was analyzed for items (intraclass correlation coefficient (ICC) and percent agreement) and dimensions (ICC and Bland-Altman plots). In general, the think-aloud interviews revealed that the COACH tool was perceived as clear, well organized, and easy to answer. Most items were understood as intended. However, seven prominent problems in the items were identified and the content of three dimensions was perceived to be of a sensitive nature. In the test-retest survey, two-thirds of the items and seven of eight dimensions were found to have an ICC agreement ranging from moderate to substantial (0.5-0.7), demonstrating that the instrument has an acceptable level of stability. This study provides evidence that the Vietnamese translation of the COACH tool is generally perceived to be clear and easy to understand and has acceptable stability. There is, however, a need to rephrase and add generic examples to clarify some items and to further review items with low ICC.


Sialic acid and N-acetylglucosamine Regulate type 1 Fimbriae Synthesis.
Type 1 fimbriae of E. coli, a chaperon-usher bacterial adhesin, are synthesized by the majority of strains of the bacterium. Although frequently produced by commensal strains, the adhesin is nevertheless a virulence factor in Extraintestinal Pathogenic E. coli (ExPEC). The role of the adhesin in pathogenesis is best understood in Uropathogenic E. coli (UPEC). Host attachment and invasion by type 1 fimbriate bacteria activates inflammatory pathways, with TLR4 signaling playing a predominant role. In a mouse model of cystitis, type 1 fimbriation not only enhances UPEC adherence to the surface of superficial umbrella cells of the bladder urothelium, but is both necessary and sufficient for their invasion. Moreover the adhesin plays a role in the formation of transient intracellular bacterial communities (IBCs) within the cytoplasm of urothelial cells as part of UPEC cycles of invasion. The expression of type 1 fimbriation is controlled by phase variation at the transcriptional level, a mode of gene regulation in which bacteria switch reversibly between fimbriate and afimbriate phases. Phase variation has been widely considered to be a mechanism enabling immune evasion. Notwithstanding the apparently random nature of phase variation, switching of type 1 fimbrial expression is nevertheless controlled by a range of environmental signals that include the amino sugars sialic acid and N-acetylglucosamine (GlcNAc). Sialic acid plays a pivotal role in innate immunity, including signaling by the toll-like receptors. Here how sialic acid and GlcNAc control type 1 fimbriation is described and the potential significance of this regulatory response is discussed.


Categorical analysis of factors affecting needs and demands for removable dentures among Alexandria Dental Research Center clientele.
An accurate assessment of dental needs is important to public health planners. With this information, it is possible to assess future treatment needs and demands for services including those for removable dentures. The present work aimed to estimate the magnitude and types of needs, and demands for partial or complete removable dentures, to study some factors that may affect the identified needs and demands for removable dentures, in addition to studying the factors that may affect satisfaction with the dentures. The present study was conducted in "Alexandria Dental Research Center". Data were collected by means of interview questionnaire, followed by dental examination of all patients attending the center for the sake of removable dental restorations for a period of 6 months. A further follow up over a period of three months was undertaken to the 330 cases recorded. About one third of the cases demanded partial and/or complete dentures and were above 60 years old. The first purpose for construction of new dentures was mastication, followed by cosmetics. Only one quarter of cases decided to have delayed immediate dentures. Diabetics and those having chronic diseases showed more demand for complete dentures. The most discriminating variable between the demand for different dentures was the missing in the lower anterior teeth followed by missing in the upper both anterior and posterior and then missing in the upper anterior teeth. Satisfaction score increased with advance of age, among males, among those for complete dentures, and those who had had previous dentures. Stepwise logistic regression revealed that the best predictor for overall satisfaction was the history of having previous dentures. Results of the present study, suggest that early screening and treatment of diabetic patients, gathering detailed information by means of a questionnaire before new dentures fabrication may be an important tool for the dentist in predicting and consequently enhancing patient satisfaction with the dentures. Health education should stress on the value of restoring missing teeth and all available options around this.


Perceived risk factors and risk pathways of Rift Valley fever in cattle in Ijara district, Kenya.
Ijara district in Kenya was one of the hotspots of Rift Valley fever (RVF) during the 2006/2007 outbreak, which led to human and animal deaths causing major economic losses. The main constraint for the control and prevention of RVF is inadequate knowledge of the risk factors for its occurrence and maintenance. This study was aimed at understanding the perceived risk factors and risk pathways of RVF in cattle in Ijara to enable the development of improved community-based disease surveillance, prediction, control and prevention. A cross-sectional study was carried out from September 2012 to June 2013. Thirty-one key informant interviews were conducted with relevant stakeholders to determine the local pastoralists' understanding of risk factors and risk pathways of RVF in cattle in Ijara district. All the key informants perceived the presence of high numbers of mosquitoes and large numbers of cattle to be the most important risk factors contributing to the occurrence of RVF in cattle in Ijara. Key informants classified high rainfall as the most important (12/31) to an important (19/31) risk factor. The main risk pathways were infected mosquitoes that bite cattle whilst grazing and at watering points as well as close contact between domestic animals and wildlife. The likelihood of contamination of the environment as a result of poor handling of carcasses and aborted foetuses during RVF outbreaks was not considered an important pathway. There is therefore a need to conduct regular participatory community awareness sessions on handling of animal carcasses in terms of preparedness, prevention and control of any possible RVF epizootics. Additionally, monitoring of environmental conditions to detect enhanced rainfall and flooding should be prioritised for preparedness.


MOCA-Peds: Development of a New Assessment of Medical Knowledge for Continuing Certification.
The American Board of Pediatrics (ABP) certifies that general and subspecialty pediatricians meet standards of excellence established by their peers. Certification helps demonstrate that a general pediatrician or pediatric subspecialist has successfully completed accredited training and fulfills continuous certification requirements (Maintenance of Certification [MOC]). One current component of the MOC program is a closed-book examination administered at a secure testing center (ie, the MOC Part 3 examination). In this article, we describe the development of an alternative to this examination termed the "Maintenance of Certification Assessment for Pediatrics" (MOCA-Peds) during 2015-2016. MOCA-Peds was conceptualized as an online, summative (ie, pass/fail), continuous assessment of a pediatrician's knowledge that would also promote learning. The system would consist of a set number of multiple-choice questions delivered each quarter, with immediate feedback on questions, rationales clarifying correct and incorrect answers, references for further learning, and peer benchmarking. Questions would be delivered quarterly and taken at any time within the quarter in a setting with Internet connectivity and on any device. As part of the development process in 2015-2016, the ABP actively recruited pediatricians to serve as members of a yearlong user panel or single-session focus groups. Refinements to MOCA-Peds were made on the basis of their feedback. MOCA-Peds is being actively piloted with pediatricians in 2017-2018. The ABP anticipates an expected launch in January 2019 of MOCA-Peds for General Pediatrics, Pediatric Gastroenterology, Child Abuse, and Pediatric Infectious Diseases with launch dates for the remaining pediatric subspecialties between 2020 and 2022.


A mcr-1-Carrying Conjugative IncX4 Plasmid in Colistin-Resistant Escherichia coli ST278 Strain Isolated From Dairy Cow Feces in Shanghai, China.
Enterobacteriaceae, including Escherichia coli, has been shown to acquire the colistin resistance gene mcr-1. A strain of E. coli, EC11, which is resistant to colistin, polymyxin B and trimethoprim-sulfamethoxazole, was isolated in 2016 from the feces of a dairy cow in Shanghai, China. Strain EC11 identifies with sequence type ST278 and is susceptible to 19 frequently used antibiotics. Whole genome sequencing of strain EC11 showed that this strain contains a 31-kb resistance plasmid, pEC11b, which belongs to the IncX4 group. The mcr-1 gene was shown to be inserted into a 2.6-kb mcr-1-pap2 cassette of pEC11b. Plasmid pEC11b also contained putative conjugal transfer components, including an oriT-like region, relaxase, type IV coupling protein, and type IV secretion system. We were successful in transferring pEC11b to E. coli C600 with an average transconjugation efficiency of 4.6 × 10-5. Additionally, a MLST-based analysis comparing EC11 and other reported mcr-positive E. coli populations showed high genotypic diversity. The discovery of the E. coli strain EC11 with resistance to colistin in Shanghai emphasizes the importance of vigilance in detecting new threats like mcr genes to public health. Detection of mcr genes helps in tracking, slowing, and responding to the emergence of antibiotic resistance in Chinese livestock farming.


Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.
To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.


Studies without internal controls.
Sometimes questions of clinical interest can be addressed only by investigations without concurrent controls that are under the supervision of the investigator (internal controls). Such studies nearly always make use of other types of comparisons (external controls), such as historical controls. In this paper we examine studies of clinical treatments that have weak internal controls or lack internal controls, as illustrated by recent examples from the Journal. These studies have a small but important and unique role in clinical investigation. Five interrelated features can add to the strength of such studies: (1) an intent by the investigator, expressed before the study, that the treatment will affect the outcomes reported; (2) planning of the analysis before the data are generated; (3) articulation of a plausible hypothesis before the results are observed; (4) a likelihood that the results would still have been of interest if they had been "opposite" in some sense; and (5) reasonable grounds for generalizing the results from the study subjects to a substantially broader group of patients. In spite of potential pitfalls, carefully selected and reported studies without internal controls can play a substantial part in the acquisition of scientific knowledge.


Corneal epithelial cell adhesion and growth on EGF-modified aminated PDMS.
Growth factor tethering has significant potential to mediate cellular responses in biomaterials and tissue engineering. We have previously demonstrated that epidermal growth factor (EGF) can be tethered to polydimethylsiloxane (PDMS) substrates and that these surfaces promoted interactions with human corneal epithelial cells in vitro. The goal of the current work was to better understand the specific effects of the tethered growth factor on the cells. The EGF was reacted with a homobifunctional N-hydroxysuccinimide (NHS) polyethylene glycol (PEG) derivative, and then bound to allyamine plasma-modified PDMS. Human corneal epithelial cells were seeded on the surfaces and cultured in serum-free medium for periods of up to 5 days. Cell growth was monitored and quantified by trypsinization and counting with a Coulter counter. Expression of matrix proteins and alpha(6)-integrins was assessed by immunostaining and confocal microscopy. A centrifugation assay was used to determine cell adhesion under an applied detachment force. Binding of EGF was found to significantly increase cell numbers and coverage across the surfaces at 5 days of culture in vitro. Immunofluorescence experiments indicate increased expression of fibronectin, laminin, and alpha(6)-integrins on the EGF-modified surfaces, and expression is localized at the cell-material interface as observed by confocal microscopy. In accordance with these results, the highest quantity of adherent cells is found on the EGF-modified subtrates at 5 days of culture. The results provide initial evidence that binding of EGF may be used to improve the epithelialization of and the adhesion of the cells on a polymeric artificial cornea device.


Insertion of Isocyanides into N-Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds.
Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, which then proceed through a key insertion of the isocyanide into a N-Si bond. The reaction is initiated by N activation of the azine, followed by nucleophilic attack of an isocyanide in a Reissert-type process. Finally, a second equivalent of the same or a different isocyanide inserts into the N-Si bond leading to the final adduct. The use of distinct nucleophiles leads to a variety of α-substituted dihydroazines after a selective cascade process. Based on computational studies, a mechanistic hypothesis for the course of these reactions was proposed. The resulting products exhibit significant activity against Trypanosoma brucei and T. cruzi, featuring favorable drug-like properties and safety profiles.


Identification of a novel MICA allele: MICA*051.
We have identified a novel MICA allele, MICA*051, detected by the polymerase chain reaction using sequence-specific primers and characterized by sequence-based typing. MICA*051 appears to be the result of a recombination between MICA*00801 and MICA*00701 at intron 2.


Aging- and gender-related modulation of RAAS: potential implications in COVID-19 disease.
Coronavirus disease 2019 (COVID-19) is a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is frequently characterized by a marked inflammatory response with severe pneumonia and respiratory failure associated with multiorgan involvement. Some risk factors predispose patients to develop a more severe infection and to an increased mortality; among them, advanced age and male gender have been identified as major and independent risk factors for COVID-19 poor outcome. The renin-angiotensin-aldosterone system (RAAS) is strictly involved in COVID-19 because angiotensin converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 and also converts pro-inflammatory angiotensin (Ang) II into anti-inflammatory Ang(1-7). In this review, we have addressed the effect of aging and gender on RAAS with emphasis on ACE2, pro-inflammatory Ang II/Ang II receptor 1 axis and anti-inflammatory Ang(1-7)/Mas receptor axis.


Theoretical bounds for the influence of tissue-level ductility on the apparent-level strength of human trabecular bone.
The role of tissue-level post-yield behavior on the apparent-level strength of trabecular bone is a potentially important aspect of bone quality. To gain insight into this issue, we compared the apparent-level strength of trabecular bone for the hypothetical cases of fully brittle versus fully ductile failure behavior of the trabecular tissue. Twenty human cadaver trabecular bone specimens (5mm cube; BV/TV=6-36%) were scanned with micro-CT to create 3D finite element models (22-micron element size). For each model, apparent-level strength was computed assuming either fully brittle (fracture with no tissue ductility) or fully ductile (yield with no tissue fracture) tissue-level behaviors. We found that the apparent-level ultimate strength for the brittle behavior was only about half the value of the apparent-level 0.2%-offset yield strength for the ductile behavior, and the ratio of these brittle to ductile strengths was almost constant (mean±SD=0.56±0.02; n=20; R(2)=0.99 between the two measures). As a result of this small variation, although the ratio of brittle to ductile strengths was positively correlated with the bone volume fraction (R(2)=0.44, p=0.01) and structure model index (SMI, R(2)=0.58, p<0.01), these effects were small. Mechanistically, the fully ductile behavior resulted in a much higher apparent-level strength because in this case about 16-fold more tissue was required to fail than for the fully brittle behavior; also, there was more tensile- than compressive-mode of failure at the tissue level for the fully brittle behavior. We conclude that, in theory, the apparent-level strength behavior of human trabecular bone can vary appreciably depending on whether the tissue fails in a fully ductile versus fully brittle manner, and this effect is largely constant despite appreciable variations in bone volume fraction and microarchitecture.


Rapid detection of DNA-interstrand and DNA-protein cross-links in mammalian cells by gravity-flow alkaline elution.
Alkaline elution is a sensitive and commonly used technique to detect cellular DNA damage in the form of DNA strand breaks and DNA cross-links. Conventional alkaline elution procedures have extensive equipment requirements and are tedious to perform. Our laboratory recently presented a rapid, simplified, and sensitive modification of the alkaline elution technique to detect carcinogen-induced DNA strand breaks. In the present study, we have further modified this technique to enable the rapid characterization of chemically induced DNA-interstrand and DNA-protein associated cross-links in cultured epithelial cells. Cells were exposed to three known DNA cross-linking agents, nitrogen mustard (HN2), mitomycin C (MMC), or ultraviolet irradiation (UV). One hour exposures of HN2 at 0.25, 1.0, and 4.0 microM or of MMC at 20, 40, and 60 microM produced a dose-dependent induction of total DNA cross-links by these agents. Digestion with proteinase K revealed that HN2 and MMC induced both DNA-protein cross-links and DNA-interstrand cross-links. Ultraviolet irradiation induced both DNA cross-links and DNA strand breaks, the latter of which were either protein and nonprotein associated. The results demonstrate that gravity-flow alkaline elution is a sensitive and accurate method to characterize the molecular events of DNA cross-linking. Using this procedure, elution of DNA from treated cells is completed in 1 hr, and only three fractions per sample are analyzed. This method may be useful as a rapid screening assay for genotoxicity and/or as an adjunct to other predictive assays for potential mutagenic or carcinogenic agents.


Dexmedetomidine for Improved Quality of Emergence From General Anesthesia: A Dose-Finding Study.
Dexmedetomidine provides smooth and hemodynamically stable emergence at the expense of hypotension, delayed recovery, and sedation. We investigated the optimal dose of dexmedetomidine for prevention of cough, agitation, hypertension, tachycardia, and shivering, with minimal side effects. In this prospective, randomized, double-blind trial, 216 adult patients were randomly assigned to dexmedetomidine 1 µg/kg (D 1), 0.5 µg/kg (D 0.5), 0.25 µg/kg (D 0.25), or control (C). During emergence, cough, agitation, hemodynamic parameters, shivering, time to extubation, and sedation scores were recorded. A total of 190 patients were analyzed. The respective incidences for the groups D 1, D 0.5, and D 0.25 versus group C were 48%, 64%, and 64% vs 84% for cough-corrected P < .003 between groups D 1 and C; 33%, 34%, and 33% vs 72% for agitation-corrected P < .003 between group C and each of the study groups; and 4%, 2%, and 7% vs 22% for shivering-corrected P = .03 and corrected P = .009 between groups D 1 and D 0.5 versus group C, respectively. The percent increase from baseline blood pressure on extubation for the 3 treatment groups was significantly lower than group C. Percent increase in heart rate was lower than control in groups D 1 and D 0.5 but not in group D 0.25. Time to extubation and sedation scores were comparable. However, more hypotension was recorded during the emergence phase in the 3 treatment groups versus group C. D 1 at the end of surgery provides the best quality of emergence from general anesthesia including the control of cough, agitation, hypertension, tachycardia, and shivering. D 0.5 also controls emergence phenomena but is less effective in controlling cough. The 3 doses do not delay extubation. However, they cause dose-dependent hypotension.


Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study.
Herpes zoster ophthalmicus (HZO), thought to be a unilateral disease, results in loss of corneal sensation, leading to neurotrophic keratopathy. This study aimed to analyze bilateral corneal nerve changes in patients with HZO by in vivo confocal microscopy (IVCM) and their correlation with corneal sensation as a measure of nerve function. Prospective, cross-sectional, controlled, single-center study. Twenty-seven eyes with the diagnosis of HZO and their contralateral clinically unaffected eyes were studied and compared with normal controls (n = 15). In vivo confocal microscopy (Confoscan 4; Nidek Technologies, Gamagori, Japan) and corneal esthesiometry (Cochet-Bonnet; Luneau Ophthalmologie, Chartres, France) of the central cornea were performed bilaterally in all patients and controls. Patients were grouped into normal (>5.5 cm), mild (>2.5-5.5 cm), and severe (<2.5 cm) loss of sensation. Changes in corneal nerve density, total nerve number, main nerve trunks, branching, and tortuosity were evaluated after IVCM and were correlated to corneal sensation, disease duration, and number of recurrences. Eyes with herpes zoster ophthalmicus had a significant (P<0.001) decrease in total nerve length (595.8±358.1 vs. 2258.4±989.0 μm/frame), total number of nerves (5.4±2.8 vs. 13.1±3.8), number of main nerve trunks (2.3±1.1 vs. 4.7±1.2), and number of nerve branches (3.2±2.3 vs. 8.4±3.7) as compared with controls. In the contralateral clinically unaffected eyes, total nerve length (1053.1±441.4 μm/frame), total number of nerves (8.3±2.9), and main nerve trunks (3.1±1.0) also were decreased significantly as compared with controls (P<0.01). Reduced nerve density, total nerve count, main trunks, and tortuosity was correlated significantly with corneal sensation across all subgroups (P<0.001). Patients with unilateral HZO demonstrated a profound and significant bilateral loss of the corneal nerve plexus as compared with controls, demonstrating bilateral changes in a clinically unilateral disease. Loss of corneal sensation strongly correlated with subbasal nerve plexus alterations as shown by IVCM. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.
Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.


Analysis of 57,148 transmissions by remote monitoring of implantable cardioverter defibrillators.
Remote monitoring of implantable cardioverter defibrillators (ICD) is designed to decrease the number of ambulatory visits and facilitate the early detection of adverse events. We examined the impact of remote monitoring on clinical workload by a comprehensive analysis of transmitted events. The study population consisted of 146 recipients of ICD capable of remote monitoring. Data were transmitted daily or in case of pre-specified events (e.g., arrhythmia, out-of-range lead and/or shock impedance). Transmitted events were classified as clinical (disease-related) or system-related. Event rates/patient/month were calculated and compared according to events classification and clinical groups. During a mean follow-up of 22 +/- 16 months, a total of 57,148 remote transmissions were recorded. Of these transmissions, 1009 (1.8%) were triggered by a pre-specified event, including induced ventricular fibrillation (VF) episodes during defibrillation threshold testing. The median number of events/patient/month was 0.14. Event rates were similar in patients with primary and secondary prevention indications for ICD (0.15 vs. 0.11). After exclusion of the induced VF episodes, 5.6% of transmitted events were classified as system-related and 94.4% as clinical. The median number of clinical events/patient/month was 0.023. The clinical event-free rates were 62% and 45%, at 1 and 4 years, respectively. Remote monitoring of ICD patients is feasible. Despite the large number of data transmissions, remote monitoring imposed a minimal additional burden on the clinical workload. The rate of triggered data transmissions by critical events was, relatively, very low.


Evaluation of treatment of colostrum-deprived kittens with equine IgG.
To evaluate equine IgG as a treatment for kittens with failure of passive transfer of immunity (FPT). 13 specific pathogen-free queens and their 77 kittens. Kittens were randomized at birth into 9 treatment groups. One group contained colostrum-fed (nursing) kittens; the other groups contained colostrum-deprived kittens that were administered supplemental feline or equine IgG PO or SC during the first 12 hours after birth. Blood samples were collected at serial time points from birth to 56 days of age for determination of serum IgG concentrations. The capacity of equine IgG to opsonize bacteria for phagocytosis by feline neutrophils was determined via flow cytometry. Kittens that received feline or equine IgG SC had significantly higher serum IgG concentrations than those of kittens that received the supplements PO. In kittens that were administered supplemental IgG SC, serum IgG concentrations were considered adequate for protection against infection. The half-life of IgG in kittens treated with equine IgG was shorter than that in kittens treated with feline IgG. Feline IgG significantly enhanced the phagocytosis of bacteria by feline neutrophils, but equine IgG did not. Serum concentrations of equine IgG that are considered protective against infection are easily attained in kittens, but the failure of these antibodies to promote bacterial phagocytosis in vitro suggests that equine IgG may be an inappropriate treatment for FPT in kittens.


An Interprofessional Curriculum to Advance Relational Coordination and Professionalism in Early-Career Practitioners.
We created a curriculum to help new physicians and nurses develop skills in interprofessional collaboration. This modular, team-based curriculum for early practitioners delivered training in the five following skill areas: listening for meaning, soliciting another's perspective, negotiating a transparent plan of care, attending to nonverbal communication and microaggression, and speaking up the hierarchy. We brought first-year medical and surgical residents and new nurses together for a 2-hour session monthly for 5 months. Each session began with an interactive large-group presentation, followed by small-group activities covering one of the five skill areas above, which had been identified as critical to interprofessional collaboration by national organizations. We measured relational coordination (RC), a validated measure of how well teams work together, before and after the curriculum was administered. We also obtained qualitative data from participant interviews and end-of-session evaluations. Participants reported that the program helped them gain an understanding of each other's roles and workflow challenges. They felt that the curriculum allowed for the cultivation of professional relationships outside the clinical environment, which improved collegiality via gains in rapport and empathy towards each other. Nurses noted increased approachability of their physician colleagues after participation. RC scores improved for the entire cohort (p = .0232). Nurses had statistically higher RC gains than interns did (p = .0055). Curriculum participants demonstrated improved RC scores and reported increased rapport with and empathy for each other. Curriculum development in this area is important because it may lead to better team-based patient care.


A primer of magnetic stimulation as a tool for neuropsychology.
Transcranial magnetic stimulation (TMS) offers the neuropsychologist a 'virtual lesion' method of investigating the effects of cortical dysfunction. Classical neuropsychology relies on patients with irreversible, and often diffuse brain lesions and these factors place limitations on the inferences that can be drawn about normal brain function. Thus the neuropsychologist is constrained by the extent to which the damaged brain undergoes reorganisation and by the inability to address questions regarding the timing of cognitive functions. TMS can disrupt cognitive functions for a few tens of milliseconds (although some effects of TMS can be seen for longer), with spatial resolution in the order of a centimetre and therefore allows one to study the role of brain areas without the masking effects of cortical reorganisation. The spatial and temporal resolutions are not unique to TMS but because TMS can be used as a temporary interference technique, it has a functional resolution with which one can address questions beyond the range of other neuroimaging and patient studies. Here we outline how TMS produces transitory 'lesion' effects, examine how the effects of stimulation spread in depth and breadth across the cortex and discuss the principles of the use of TMS in neuropsychology. Finally, we also itemise some issues of safety.


Validation of the AUDIT-C in adults seeking help with their drinking online.
The abbreviated Alcohol Use Disorder Identification Test for Consumption (AUDIT-C) is rapidly becoming the alcohol screening tool of choice for busy practitioners in clinical settings and by researchers keen to limit assessment burden and reactivity. Cut-off scores for detecting drinking above recommended limits vary by population, setting, country and potentially format. This validation study aimed to determine AUDIT-C thresholds that indicated risky drinking among a population of people seeking help over the Internet. The data in this study were collected in the pilot phase of the Down Your Drink trial, which recruited people seeking help over the Internet and randomised them to a web-based intervention or an information-only website. Sensitivity, specificity, and positive and negative likelihood ratios were calculated for AUDIT-C scores, relative to weekly consumption that indicated drinking above limits and higher risk drinking. Receiver-operating characteristic (ROC) curves were created to assess the performance of different cut-off scores on the AUDIT-C for men and women. Past week alcohol consumption was used as the reference-standard and was collected via the TOT-AL, a validated online measure of past week drinking. AUDIT-C scores were obtained from 3720 adults (2053 female and 1667 male) searching the internet for help with drinking, mostly from the UK. The area under the ROC curve for risky drinking was 0.84 (95% CI 0.80, 0.87) (female) and 0.80 (95% CI 0.76, 0.84) (male). AUDIT-C cut-off scores for detecting risky drinking that maximise the sum of sensitivity and specificity were ≥8 for women and ≥8 for men; whereas those identifying the highest proportion of correctly classified individuals were ≥4 for women and ≥5 for men. AUDIT-C cut-off scores for detecting higher risk drinking were also calculated. AUDIT-C cut-off scores for identifying alcohol consumption above weekly limits in this largely UK based study population were substantially higher than those reported in other validation studies. Researchers and practitioners should select AUDIT-C cut-off scores according to the purpose of identifying risky drinkers and hence the relative importance of sensitivity and/or specificity.


Unravelling barriers to accessing HIV prevention services experienced by African and Caribbean communities in Canada: lessons from Toronto.
Barriers to accessing HIV-prevention services, experienced by African and Caribbean communities in Canada, is an issue warranting sustained research. This study seeks to achieve a better understanding of the nature of HIV-prevention services in Canada, and to explore the dynamics, which underpin barriers to accessing these services confronting African and Caribbean populations in Toronto (Canada). This study also endeavours to assess what is being done to reduce these barriers. Semi-structured qualitative interviews with 7 professionals and community workers who were involved in organizing, researching and delivering HIV-prevention services were conducted for this study. Four themes pertaining to barriers to accessing HIV-prevention services, including, levels of cultural competence and sensitivity among service providers; cultural and social stigma directed at persons living with HIV/AIDS; various social determinants of health, including gender, race and precarious immigration status'; as well as constrained funding resources that are available for service providers; were uncovered in the findings of the study. The paper concludes that several health promotion and health education initiatives exist, which can help reduce these barriers to HIV-prevention service access for these populations. However, in order to ensure their effectiveness there will be much needed involvement from community and other relevant government agencies, which will need to work separately and in conjunction with one another, in order to tackle some of the broader issues that affect these populations.


Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study.
The current study was designed to examine whether a combination of three nutrients, consisting of beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of leucine, L-glutamine (Gln) and L-arginine (Arg), each of which has been previously shown to slow muscle proteolysis, could synergistically alter the course of muscle wasting in patients with established acquired immunodeficiency syndrome (AIDS). Sixty-eight human immunodeficiency virus (HIV)-infected patients with a documented weight loss of at least 5% in the previous 3 months were recruited from the HIV clinic at Nassau County Medical Center. The subjects were randomly assigned in a double-blind fashion to receive either placebo containing maltodextrin or the nutrient mixture (HMB/Arg/Gln) containing 3 g HMB, 14 g L-glutamine, and 14 g L-arginine given in two divided doses daily for 8 weeks. Body weights (BW) were recorded weekly and lean body mass (LBM) and fat mass (FM) were measured by air displacement plethysmography and by a single computerized tomography (CT) slice through the thigh at 0, 4, and 8 weeks. Forty-three subjects completed the 8-week protocol, (placebo, n = 21; HMB/Arg/Gln, n = 22). At 8 weeks, the subjects consuming the HMB/Arg/Gln mixture gained 3.0 +/- 0.5 kg of BW while those supplemented with the placebo gained 0.37 +/- 0.84 kg (p = .009). The BW gain in the HMB/Arg/Gln-treated subjects was predominantly LBM (2.55 +/- 0.75 kg) compared with the placebo-supplemented subjects who lost lean mass (-0.70 +/- 0.69 kg, p = .003). No significant change in FM gain was observed (0.43 +/- 0.83 kg for the group receiving HMB/Arg/Gln and 1.07 +/- 0.64 kg for the group receiving the placebo, p > .20). Similar percentage changes in muscle mass and fat mass were observed with CT scans. Immune status was also improved as evident by an increase in CD3 and CD8 cells and a decrease in the HIV viral load with HMB/Arg/Gln supplementation. The data indicate that the HMB/Arg/Gln mixture can markedly alter the course of lean tissue loss in patients with AIDS-associated wasting.


15N Hyperpolarization of Imidazole-15N2 for Magnetic Resonance pH Sensing via SABRE-SHEATH.
15N nuclear spins of imidazole-15N2 were hyperpolarized using NMR signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH). A 15N NMR signal enhancement of ∼2000-fold at 9.4 T is reported using parahydrogen gas (∼50% para-) and ∼0.1 M imidazole-15N2 in methanol:aqueous buffer (∼1:1). Proton binding to a 15N site of imidazole occurs at physiological pH (pKa ∼ 7.0), and the binding event changes the 15N isotropic chemical shift by ∼30 ppm. These properties are ideal for in vivo pH sensing. Additionally, imidazoles have low toxicity and are readily incorporated into a wide range of biomolecules. 15N-Imidazole SABRE-SHEATH hyperpolarization potentially enables pH sensing on scales ranging from peptide and protein molecules to living organisms.


Altered d-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer's disease detected by dynamic glucose-enhanced MRI.
Altered cerebral glucose uptake is one of the hallmarks of Alzheimer's disease (AD). A dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) approach was developed to simultaneously monitor d-glucose uptake and clearance in both brain parenchyma and cerebrospinal fluid (CSF). We observed substantially higher uptake in parenchyma of young (6 months) transgenic AD mice compared to age-matched wild-type (WT) mice. Notably lower uptakes were observed in parenchyma and CSF of old (16 months) AD mice. Both young and old AD mice had an obviously slower CSF clearance than age-matched WT mice. This resembles recent reports of the hampered CSF clearance that leads to protein accumulation in the brain. These findings suggest that DGE MRI can identify altered glucose uptake and clearance in young AD mice upon the emergence of amyloid plaques. DGE MRI of brain parenchyma and CSF has potential for early AD stratification, especially at 3T clinical field strength MRI.


Farmers without borders-genetic structuring in century old barley (Hordeum vulgare).
The geographic distribution of genetic diversity can reveal the evolutionary history of a species. For crop plants, phylogeographic patterns also indicate how seed has been exchanged and spread in agrarian communities. Such patterns are, however, easily blurred by the intense seed trade, plant improvement and even genebank conservation during the twentieth century, and discerning fine-scale phylogeographic patterns is thus particularly challenging. Using historical crop specimens, these problems are circumvented and we show here how high-throughput genotyping of historical nineteenth century crop specimens can reveal detailed geographic population structure. Thirty-one historical and nine extant accessions of North European landrace barley (Hordeum vulgare L.), in total 231 individuals, were genotyped on a 384 single nucleotide polymorphism assay. The historical material shows constant high levels of within-accession diversity, whereas the extant accessions show more varying levels of diversity and a higher degree of total genotype sharing. Structure, discriminant analysis of principal components and principal component analysis cluster the accessions in latitudinal groups across country borders in Finland, Norway and Sweden. FST statistics indicate strong differentiation between accessions from southern Fennoscandia and accessions from central or northern Fennoscandia, and less differentiation between central and northern accessions. These findings are discussed in the context of contrasting historical records on intense within-country south to north seed movement. Our results suggest that although seeds were traded long distances, long-term cultivation has instead been of locally available, possibly better adapted, genotypes.


Laparoscopic hysterectomy for large uteri: Outcomes and techniques.
The aim of this study was to analyse our data of laparoscopic hysterectomy for large uteri (>16 weeks size) regarding their perioperative outcomes and possible factors for conversions to open surgery over 5 years. It also describes our techniques for the feasibility of performing such hysterectomies by the minimally invasive way. A five-year retrospective chart review was performed at the Minimal Access and Robotic Surgery Unit of the Department of Gynecology at Apollo Hospital, Hyderabad. Demographic and pre-operative and post-operative data were recorded. Clinical assessment including bimanual examination and surgery was made by a single senior surgeon. Intra-operative conversions, complications and post-operative complications were recorded. A total of 128 women were included in this study, 5 patients underwent robotic-assisted hysterectomy. The average age was 44.4, body mass index - was 27.6 and size of the uterus was 17.5 weeks. The most common diagnosis was leiomyoma. The median Operating room (OR) time was 107 min. There was a need for myomectomy in 39.8%, extensive adhesiolysis in 33.6% and dense bladder adhesion in 26.6%. The average drop in haemoglobin was 1.72 g%, and hospital stay was 2 days. The specimen was removed by vaginal morcellation (2 cases via an umbilical port). Conversion to open surgery was required in 10.9% of cases. The conversion was significantly correlated with excessive haemorrhage and bladder injury but not with difficult hysterectomy, difficult bladder dissection or adhesions. There were 3 cases of bladder injury detected and managed intraoperatively. Laparoscopic hysterectomy is technically feasible and safe procedure for large uteri. The learning curve is about 50 cases and can be performed by experienced surgeons regardless of the size, number or location of the myomas without much morbidity.


Factors associated with non-adherence to HBV antiviral therapy.
HBV antiviral therapy has the potential to reduce the burden of HBV-related liver disease by suppressing HBV DNA replication to undetectable levels, reducing the progression of liver fibrosis and reducing the risk of hepatocellular carcinoma (HCC) development. Treatment outcomes and long-term benefits require adherence to medication regimens. This study aimed to identify the prevalence and factors associated with non-adherence to antiviral therapy. A cross-sectional survey of patients receiving HBV antiviral therapies was conducted in three Sydney hospitals. Participants were asked to complete an online questionnaire. Logistic regression was used to assess the associations between non-adherence (defined as missing more than 1 day of medication in the last 30 days) and demographic, socio-economic, disease, treatment, health-care system and individual-related factors. Of the 277 participants, 66 (23.8%) were non-adherent, missing a mean 1.7 days of medication (sd 4.8) in the last 30 days. In multivariate analysis, non-adherent behaviour declined with age (odds ratio [OR] 0.9, 95% CI 0.97, 0.99; P<0.013). Participants who reported having no established routine to take their medication (OR 5.0, 95% CI 1.4, 17.4; P<0.012) and having inadequate health literacy (OR 2.7, 95% CI 1.3, 5.5; P<0.007) were more likely to be non-adherent. Almost a quarter of participants in the current study were non-adherent. Adherence is potentially modifiable through person-centred education, collaborative models of patient care and interventions designed to improve health literacy and establish medication routines. Findings have the potential to improve health service delivery to patients at risk of non-adherence to HBV antiviral therapy.


Synchronization likelihood with explicit time-frequency priors.
Cognitive processing requires integration of information processed simultaneously in spatially distinct areas of the brain. The influence that two brain areas exert on each others activity is usually governed by an unknown function, which is likely to have nonlinear terms. If the functional relationship between activities in different areas is dominated by the nonlinear terms, linear measures of correlation may not detect the statistical interdependency satisfactorily. Therefore, algorithms for detecting nonlinear dependencies may prove invaluable for characterizing the functional coupling in certain neuronal systems, conditions or pathologies. Synchronization likelihood (SL) is a method based on the concept of generalized synchronization and detects nonlinear and linear dependencies between two signals (Stam, C.J., van Dijk, B.W., 2002. Synchronization likelihood: An unbiased measure of generalized synchronization in multivariate data sets. Physica D, 163: 236-241.). SL relies on the detection of simultaneously occurring patterns, which can be complex and widely different in the two signals. Clinical studies applying SL to electro- or magnetoencephalography (EEG/MEG) signals have shown promising results. In previous implementations of the algorithm, however, a number of parameters have lacked a rigorous definition with respect to the time-frequency characteristics of the underlying physiological processes. Here we introduce a rationale for choosing these parameters as a function of the time-frequency content of the patterns of interest. The number of parameters that can be arbitrarily chosen by the user of the SL algorithm is thereby decreased from six to two. Empirical evidence for the advantages of our proposal is given by an application to EEG data of an epileptic seizure and simulations of two unidirectionally coupled Hénon systems.


Antioxidant enzyme activity and coronary heart disease: meta-analyses of observational studies.
Controversial data exist concerning the relation between the activities of scavenger antioxidant enzymes and coronary heart disease (CHD) risk. The authors report updated meta-analyses of studies assessing the activities of 3 antioxidant enzymes--glutathione peroxidase, superoxide dismutase, and catalase--and CHD risk. Computer-based and manual searches of the relevant literature from January 1966 to January 2008 were performed. Studies assessing glutathione peroxidase, superoxide dismutase, and catalase activities in cells or biologic fluids and clinical CHD outcomes were selected. Pooled odds ratios for CHD were calculated by using an inverse-variance-weighted random-effects model. Forty-two case-control studies and 3 prospective studies were included. The pooled odds ratios for CHD associated with a 1-standard-deviation increase in glutathione peroxidase, superoxide dismutase, and catalase activity levels were 0.51 (95% confidence interval: 0.35, 0.75), 0.48 (95% confidence interval: 0.32, 0.72), and 0.32 (95% confidence interval: 0.16, 0.61), respectively, with substantial between-study heterogeneity (I(2) > 90% for the 3 enzymes). These findings were remarkably robust in the sensitivity analysis. The authors' meta-analyses support an inverse association between circulating levels of superoxide dismutase, glutathione peroxidase, and catalase activities with CHD and emphasize the need for additional high-quality prospective studies.


Adductor Pollicis Muscle Thickness for nutritional assessment: a systematic review.
The aim of this study is to systematically review the scientific findings about the efficacy of the measure of the Adductor Pollicis Muscle Thickness for nutritional assessment of individuals in various clinical conditions. Systematic review study performed according to the methodology Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 13 original articles published between 2004 and 2016 were included. The measure was associated/correlated to parameters of nutritional status (such as weight, body mass index and Global Subjective Assessment) and muscle mass markers (such as circumference brachial muscle circumference, brachial muscle area, calf circumference, and muscle mass). All these correlations were weak or moderate. The measurement can be used in different populations, being able to estimate nutritional status and muscle mass. However, it is suggested that it be used in a complementary way to the nutritional evaluation, not constituting a single diagnostic/monitoring parameter.


Determination of critical diameters for intrinsic carrier diffusion-length of GaN nanorods with cryo-scanning near-field optical microscopy.
Direct measurements of carrier diffusion in GaN nanorods with a designed InGaN/GaN layer-in-a-wire structure by scanning near-field optical microscopy (SNOM) were performed at liquid-helium temperatures of 10 K. Without an applied voltage, intrinsic diffusion lengths of photo-excited carriers were measured as the diameters of the nanorods differ from 50 to 800 nm. The critical diameter of nanorods for carrier diffusion is concluded as 170 nm with a statistical approach. Photoluminescence spectra were acquired for different positions of the SNOM tip on the nanorod, corresponding to the origins of the well-defined luminescence peaks, each being related to recombination-centers. The phenomenon originated from surface oxide by direct comparison of two nanorods with similar diameters in a single map has been observed and investigated.


Gallium assisted plasma enhanced chemical vapor deposition of silicon nanowires.
Silicon nanowires have been grown with gallium as catalyst by plasma enhanced chemical vapor deposition. The morphology and crystalline structure has been studied by electron microscopy and Raman spectroscopy as a function of growth temperature and catalyst thickness. We observe that the crystalline quality of the wires increases with the temperature at which they have been synthesized. The crystalline growth direction has been found to vary between <111> and <112>, depending on both the growth temperature and catalyst thickness. Gallium has been found at the end of the nanowires, as expected from the vapor-liquid-solid growth mechanism. These results represent good progress towards finding alternative catalysts to gold for the synthesis of nanowires.


A pilot study on non-invasive in situ detection of phytochemicals and plant endogenous status using fiber optic infrared spectroscopy.
Traditional methods for assessing plant health often lack the necessary attributes for continuous and non-destructive monitoring. In this pilot study, we present a novel technique utilizing a customized fiber optic probe based on attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) with a contact force control unit for non-invasive and continuous plant health monitoring. We also developed a normalized difference mid-infrared reflectance index through statistical analysis of spectral features, enabling differentiation of drought and age conditions in plants. Our research aims to characterize phytochemicals and plant endogenous status optically, addressing the need for improved analytical measurement methods for in situ plant health assessment. The probe configuration was optimized with a triple-loop tip and a 3 N contact force, allowing sensitive measurements while minimizing leaf damage. By combining polycrystalline and chalcogenide fiber probes, a comprehensive wavenumber range analysis (4000-900 cm-1) was achieved. Results revealed significant variations in phytochemical composition among plant species, for example, red spinach with the highest polyphenolic content and green kale with the highest lignin content. Petioles displayed higher lignin and cellulose absorbance values compared to veins. The technique effectively monitored drought stress on potted green bok choy plants in situ, facilitating the quantification of changes in water content, antioxidant activity, lignin, and cellulose levels. This research represents the first demonstration of the potential of fiber optic ATR-FTIR probes for non-invasive and rapid plant health measurements, providing insights into plant health and advancements in quantitative monitoring for indoor farming practices, bioanalytical chemistry, and environmental sciences.


Citalopram treatment of fluoxetine nonresponders.
We assessed the tolerability and utility of switching fluoxetine nonresponders to citalopram the day that fluoxetine therapy was stopped. Fifty-eight outpatients with DSM-IV major depressive episode and prospectively confirmed nonresponse to fluoxetine (mean final dose = 31 mg/day) were switched directly to citalopram (20 mg/day). Of the 58 patients, 44 (76%) had never been successfully treated with antidepressant medication. During a 12-week open-label treatment period, citalopram could be titrated up to a maximum dose of 60 mg/day. Response was evaluated using the Clinical Global Impressions (CGI) scale, the 24-item Hamilton Rating Scale for Depression, and several other measures. Eighty-one percent (N = 47) completed the trial, and citalopram (mean dose = 38.8 mg/day) was well tolerated. The intent-to-treat CGI response rate was 46% (26/57) at week 6 and 63% (36/57) at study endpoint; the completer response rate was 76% among the 47 patients who completed the 12-week trial. Improvement from baseline on all dependent measures was statistically significant after the first week of citalopram treatment. Fluoxetine nonresponders can be quickly switched to citalopram, with good tolerability and reasonable chance of therapeutic benefit. Further work is necessary to assess the merits of this treatment strategy relative to other options.


Adiponectin prevents diabetic premature senescence of endothelial progenitor cells and promotes endothelial repair by suppressing the p38 MAP kinase/p16INK4A signaling pathway.
A reduced number of circulating endothelial progenitor cells (EPCs) are casually associated with the cardiovascular complication of diabetes. Adiponectin exerts multiple protective effects against cardiovascular disease, independent of its insulin-sensitizing activity. The objective of this study was to investigate whether adiponectin plays a role in modulating the bioavailability of circulating EPCs and endothelial repair. Adiponectin knockout mice were crossed with db(+/-) mice to produce db/db diabetic mice without adiponectin. Circulating number of EPCs were analyzed by flow cytometry. Reendothelialization was evaluated by staining with Evans blue after wire-induced carotid injury. In adiponectin knockout mice, the number of circulating EPCs decreased in an age-dependent manner compared with the wild-type controls, and this difference was reversed by the chronic infusion of recombinant adiponectin. In db/db diabetic mice, the lack of adiponectin aggravated the hyperglycemia-induced decrease in circulating EPCs and also diminished the stimulatory effects of the PPARγ agonist rosiglitazone on EPC production and reendothelialization. In EPCs isolated from both human peripheral blood and mouse bone marrow, treatment with adiponectin prevented high glucose-induced premature senescence. At the molecular level, adiponectin decreased high glucose-induced accumulation of intracellular reactive oxygen species and consequently suppressed activation of p38 MAP kinase (MAPK) and expression of the senescence marker p16(INK4A). Adiponectin prevents EPC senescence by inhibiting the ROS/p38 MAPK/p16(INK4A) signaling cascade. The protective effects of adiponectin against diabetes vascular complications are attributed in part to its ability to counteract hyperglycemia-mediated decrease in the number of circulating EPCs.


Substantial Toxic Effect of Water-Pipe Smoking on the Early Stage of Embryonic Development.
Water-pipe smoking (WPS) is the most widespread tobacco use in the Middle-East, and is rapidly spreading globally. Smoke from WP contains most of the compounds present in cigarette smoke, although in different proportions. WPS is associated with the risk of several human diseases; however, its impact on the early stage of normal development has not been investigated yet. Thus, in this investigation, we assess the effect of WPS on the embryo at the early stage of development. Chicken embryos at 3 days of incubations were used in this study. Meanwhile, we explored the outcome of WPS on angiogenesis using the chorioallantoic membrane (CAM) of the chicken embryos. Finally, quantitative real-time polymerase chain reaction was used to study the regulation of some key control genes of cell proliferation, apoptosis, and migration. Our data reveal that WPS inhibits angiogenesis of the CAM and in embryos in comparison with their matched controls; in addition, WPS-exposed embryos show slight reduction in their sizes. We also noted that around 80% of WPS-exposed embryos die before 10 days of incubation. More significantly, WPS induces upregulations of BCL-2, Caspase-8, ATF-3, INHIB-A, and Cadherin 6 genes, which are important key regulators of cell apoptosis, proliferation, and migration. Our data reveal, for the first time, that WPS has very toxic effects during the early stage of embryogenesis. Thus, we believe that further studies are required to elucidate the pathogenic effect of WPS on human health especially on the embryo at the early stage of its development. This investigation addresses an important gap on the outcome of WPS during the early stage of embryogenesis. Data of this study point out that WPS can have a very toxic effect on the embryo at this stage. Additionally, results from this report display for the first time that WPS can damage normal angiogenesis of the embryo thus provoking a significant number of embryonic death. Moreover, this study reveals that this effect can occur via the deregulation of several genes related to cell apoptosis, proliferation, and migration.


Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency.
Mitochondrial defects associated with respiratory chain complex I deficiency lead to heterogeneous fatal syndromes. While the role of NDUFS8, an essential subunit of the core assembly of the complex I, is established in mitochondrial diseases, the mechanisms underlying neuropathology are poorly understood. We developed a Drosophila model of NDUFS8 deficiency by knocking down the expression of its fly homologue in neurons or in glial cells. Downregulating ND23 in neurons resulted in shortened lifespan, and decreased locomotion. Although total brain ATP levels were decreased, histological analysis did not reveal any signs of neurodegeneration except for photoreceptors of the retina. Interestingly, ND23 deficiency-associated phenotypes were rescued by overexpressing the glucose transporter hGluT3 demonstrating that boosting glucose metabolism in neurons was sufficient to bypass altered mitochondrial functions and to confer neuroprotection. We then analyzed the consequences of ND23 knockdown in glial cells. In contrast to neuronal knockdown, loss of ND23 in glia did not lead to significant behavioral defects nor to reduced lifespan, but induced brain degeneration, as visualized by numerous vacuoles found all over the nervous tissue. This phenotype was accompanied by the massive accumulation of lipid droplets at the cortex-neuropile boundaries, suggesting an alteration of lipid metabolism in glia. These results demonstrate that complex I deficiency triggers metabolic alterations both in neurons and glial cells which may contribute to the neuropathology.


McbR/YncC: implications for the mechanism of ligand and DNA binding by a bacterial GntR transcriptional regulator involved in biofilm formation.
MqsR-controlled colanic acid and biofilm regulator (McbR, also known as YncC) is the protein product of a highly induced gene in early Escherichia coli biofilm development and has been regarded as an attractive target for blocking biofilm formation. This protein acts as a repressor for genes involved in exopolysaccharide production and an activator for genes involved in stress response. To better understand the role of McbR in governing the switch from exponential growth to the biofilm state, we determined the crystal structure of McbR to 2.1 Å. The structure reveals McbR to be a member of the FadR C-terminal domain (FCD) family of the GntR superfamily of transcriptional regulators (this family was named after the first identified member, GntR, a transcriptional repressor of the gluconate operon of Bacillus subtilis). Previous to this study, only six of the predicted 2800 members of this family had been structurally characterized. Here, we identify the residues that constitute the McbR effector and DNA binding sites. In addition, comparison of McbR with other members of the FCD domain family shows that this family of proteins adopts highly distinct oligomerization interfaces, which has implications for DNA binding and regulation.