Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions.
Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts.


Determinants of heart failure self-care behaviour in community-based patients: a cross-sectional study.
Self-care behaviour in patients with heart failure (HF) represents a series of specific actions that patients should take, as an important treatment component. The aim of this study was to identify potential determinants of HF self-care in ambulatory patients with stable systolic HF. In a cross-sectional study of 318 patients with chronic systolic HF recruited in 48 German primary care practices, we evaluated the patient-reported European HF Self-care Behaviour scale (EHFScBs) assessments (range 12-60, where lower scores indicate better self-care). Potential determinants included socio-demographic (e.g. age, living status), clinical (e.g. NYHA class, LVEF, NT-proBNP levels, co-morbidities), behavioural (e.g. smoking and alcohol intake), psychosocial (SF-36 scales and KCCQ domains, e.g. quality of life and self-efficacy) and depression status (PHQ-D), plus previous health care utilisation. Mixed regression modelling was applied. Patients had a mean (SD) age of 69.0 (10.4) years and were 71% male. They had a good overall EHFScBs score of 24.7 (7.8) (n=274). In the final regression model (n=271), six determinants were retained (β; descriptive p-value): self-efficacy (-0.24; <.001), age (-0.22; <.001), prosthetic heart valve (-0.14; .01), referrals to cardiologists (-0.14; .02), peripheral arterial disease (0.13; .03) and quality of life (0.16; .02). In this exploratory cross-sectional study, the potential non-modifiable and modifiable risk factors and resources involved in patients' HF self-care were at the individual and organisational level. Self-efficacy and quality of life are potentially modifiable, so these could be targeted for improvement by enhancing patient motivation, HF education and further supporting a collaborative care approach.


Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media.
To compare immediate with delayed prescribing of antibiotics for acute otitis media. Open randomised controlled trial. General practices in south west England. 315 children aged between 6 months and 10 years presenting with acute otitis media. Two treatment strategies, supported by standardised advice sheets-immediate antibiotics or delayed antibiotics (antibiotic prescription to be collected at parents' discretion after 72 hours if child still not improving). Symptom resolution, absence from school or nursery, paracetamol consumption. On average, symptoms resolved after 3 days. Children prescribed antibiotics immediately had shorter illness (-1.1 days (95% confidence interval -0.54 to -1.48)), fewer nights disturbed (-0.72 (-0.30 to -1.13)), and slightly less paracetamol consumption (-0.52 spoons/day (-0.26 to -0.79)). There was no difference in school absence or pain or distress scores since benefits of antibiotics occurred mainly after the first 24 hours-when distress was less severe. Parents of 36/150 of the children given delayed prescriptions used antibiotics, and 77% were very satisfied. Fewer children in the delayed group had diarrhoea (14/150 (9%) v 25/135 (19%), chi(2)=5.2, P=0.02). Fewer parents in the delayed group believed in the effectiveness of antibiotics and in the need to see the doctor with future episodes. Immediate antibiotic prescription provided symptomatic benefit mainly after first 24 hours, when symptoms were already resolving. For children who are not very unwell systemically, a wait and see approach seems feasible and acceptable to parents and should substantially reduce the use of antibiotics for acute otitis media.


The impact of placement stability on behavioral well-being for children in foster care.
The problems children have upon entering foster care can potentially explain prior research findings that frequent placement changes are associated with poor outcomes. This study sought to disentangle this cascading relationship in order to identify the independent impact of placement stability on behavioral outcomes downstream. Placement stability over the first 18 months in out-of-home care for 729 children from the National Survey of Child and Adolescent Well-being was categorized as early stability (stable placement within 45 days), late stability (stable placement beyond 45 days), or unstable (never achieving stability). Propensity scores predicting placement instability based on baseline attributes were divided into risk categories and added to a logistic regression model to examine the independent association between placement stability and behavioral well-being using the Child Behavior Checklist and temperament scores from the National Longitudinal Survey of Youth. Half (52%) of the children achieved early stability, 19% achieved later stability, and 28% remained unstable. Early stabilizers were more likely to be young, have normal baseline behavior, have no prior history with child welfare, and have birth parents without mental health problems. After accounting for baseline attributes, stability remained an important predictor of well-being at 18 months. Unstable children were more likely to have behavior problems than children who achieved early stability across every level of risk for instability. Among low-risk children, the probability of behavioral problems among early stabilizers was 22%, compared to 36% among unstable children, showing a 63% increase in behavior problems due to instability alone. Children in foster care experience placement instability unrelated to their baseline problems, and this instability has a significant impact on their behavioral well-being. This finding would support the development of interventions that promote placement stability as a means to improve outcomes among youth entering care.


Effect of airborne-particle abrasion of a titanium base abutment on the stability of the bonded interface and retention forces of crowns after artificial aging.
Published data have shown that a mechanical surface treatment of titanium surfaces increases bonding potential. However, most of the studies are based on shear or tensile tests performed on flat-surfaced specimens and do not take into consideration the retention given by the titanium base (ti-base) axial walls and the thermomechanical loading seen in a clinical setting. The purpose of this in vitro study was to evaluate the influence of different airborne-particle abrasion (APA) methods of the ti-base surface on the stability of the bonded interface and retention forces between these titanium bases and lithium disilicate crowns after thermomechanical aging. Sixty internal connection implants (Conelog) were restored with lithium disilicate crowns and bonded to the corresponding ti-bases (Conelog). The ti-bases were divided into 4 groups (n=15), 3 experimental groups applying different APA methods, 30-μm silica-modified Al2O3 particles (CoJet) (30-SiO-AlO), 50-μm Al2O3 (Cobra Aluoxyd) (50-AlO), 110-μm silica-modified Al2O3 particles (Rocatec Plus) (110-SiO-AlO), and 1 control group (NoT). Ti-bases were airborne-particle abraded (10 seconds, 0.25 MPa at a 10-mm distance) under standardized conditions in a custom-made APA device. All crowns were cemented with a resin cement (Multilink Hybrid Abutment). After aging (1 200 000 cycles, 49 N, 1.67 Hz; 5 °C-55 °C, 120 seconds), all specimens were assessed for the presence of bond failures by optical microscopy (×50). The retention forces (N) were tested by using a pull-off test (0.5mm/min). Modes of failure were classified (Type 1, 2, or 3). An additional ti-base representing each group was prepared for surface roughness (μm) calculation (Ra, Rc, Rz) with a noncontact laser profilometer, and representative scanning electron microscope (SEM) images were recorded (×1000). Chi-squared tests were performed to analyze the bonded interface failure and modes of failure, and a Kruskal-Wallis test was selected to evaluate retention force values (α=.05). The percentages of bonding failure after aging were 73.3% (NoT), 40% (30-SiO-AlO), 6.7% (50-AlO), and 40% (110-SiO-AlO). The stability of the bonded interface was influenced by the APA method applied (P<.05). Mean ±standard deviation retention force values varied from 206.3 ±86.3 N (NoT) to 420 ±139.5 N (50-AlO), and the differences between these 2 groups were significant (P<.05). Modes of failure were predominantly Type 2 (30-SiO-AlO; 50-AlO; 110-SiO-AlO) and Type 3 (NoT). Airborne-particle abrasion of the titanium surface increased the bond stability and retention forces between the ti-base and the respective crown. The use of 50-μm Al2O3 provided the most stable bonded interface among the different treatments.


Probiotic lactobacilli in breast milk and infant stool in relation to oral intake during the first year of life.
This is to identify factors affecting the prevalence of Lactobacillus reuteri in maternal faeces and breast milk and infant faeces after oral supplementation with L reuteri and to assess the influence on microbial ecology, particularly Clostridium difficile and Bifidobacterium colonization. In this double-blind trial, 232 mothers with a family history of atopic disease were randomized to a daily intake of either L reuteri American-type culture collection (ATCC) 55730 (1 x 10 colony-forming units [CFU]) or placebo for the last 4 weeks of pregnancy. Their babies then continued with the same study product daily from birth until 12 months of age. Bacterial counts and prevalence were assessed in maternal breast milk and faeces and infant faeces, using conventional cultivation methods. The prevalence of L reuteri was higher during the first year of life in the stool samples from infants in the active as compared with the placebo-treated group. The highest prevalence was recorded at 5 to 6 days of age (82% in the treated vs 20% in the placebo group, P < 0.001). Lactobacillus reuteri was isolated from 12% and 2%, respectively, in the colostrum samples (P < 0.05). Breast-feeding seemed to reduce faecal L reuteri counts, although antibiotics did not influence the levels of L reuteri. The administration of L reuteri did not affect bifidobacteria or C difficile colonization. Lactobacillus reuteri may be detected in breast milk after oral supplementation to the mother and in almost all infants after oral supplementation during the first year of life, as well as occasionally in many untreated infants.


The effects of tobacco control policies on retailer sales to minors in the USA, 2015.
Under the 2009 Family Smoking Prevention and Tobacco Control Act, the Food and Drug Administration (FDA) has been routinely inspecting tobacco retailers' compliance with under-age sales laws. We seek to identify factors associated with Retail Violation Rate for sale to minors (RVRm). We collected the tobacco retailer inspection data for 2015 from the FDA compliance check database. RVRm was calculated at the census tract level and overlaid with tobacco regulations and youth smoking prevalence at the state level. Multi-level spatial analysis was performed to examine the impacts of tobacco jurisdiction variations, youth smoking rates and neighbourhood social characteristics on RVRm. A total of 136 816 compliance checks involving minors conducted by the FDA in 2015 were analysed. A higher RVRm was associated with higher youth smoking prevalence (aRR=1.04, p<0.0001). Tobacco regulations show significant relationships with RVRm. For every one dollar increase in cigarette tax per pack, the likelihood of retail violations was reduced by 2% (aRR=0.98, p=0.03). For every 10% increase in tobacco prevention spending towards Centers for Disease Control recommended funding targets, the likelihood of retail violations was reduced by 1% (aRR=0.99, p=0.01). RVRm increased in states that enacted stronger smoke-free air policies (aRR=1.08, p<0.0001). We observed associations of tobacco regulations and neighbourhood social characteristics with tobacco retailers' compliance with under-age sales laws. This study provides evidence to support stronger tobacco regulations and control policies in reducing youth access to tobacco products.


Endovascular versus operative treatment of cerebral aneurysms: a comparison of results from a low-volume neurosurgical centre.
Subarachnoid haemorrhage is a debilitating disease. The treatment options include surgical clipping or endovascular embolisation. Still, many controversies exist about which method is more convenient. In the retrospective study from January 2006 to December 2013, 129 patients with subarachnoid haemorrhage were analysed. They were classified according to the WFNS grade and Fisher scale. The diagnosis of intracranial aneurysms was based on computerised tomographic angiography and digital subtraction angiography. All patients received the standard therapy against vasospasm. The treatment outcome was evaluated with Glasgow Outcome Scale. Of 129 patients, surgery was employed in 40, endovascular obliteration in 86 patients and 3 patients received both forms of treatment. Four factors were statistically significant for worse results in the univariate analysis: the age, WFNS grade, Fisher grade and the presence of clinical vasospasm. In the multivariate analysis, only the age, WFNS grade and the presence of clinical vasospasm remained statistically significant for the outcome. There was a trend towards better outcome for the patients that had endovascular treatment compared with patients who were treated surgically, although the difference was not statistically significant. Although the endovascular embolisation in relation to the surgical clipping is becoming a more popular treatment method for ruptured cerebral aneurysms it cannot offer reliable endovascular exclusion in all types of aneurysms. Based on our experience, it is therefore necessary to look at these two methods as complementary that may both be used separately or in combination for the well-being of the patient.


Metabolic syndrome and related risk factors among adults in the northern West Bank, a cross-sectional study.
Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors that includes central obesity, insulin resistance, dyslipidaemia and hypertension. The aim of this study was to establish the prevalence of MetS and its associated risk factors among adult Palestinians using the International Diabetes Federation definition. A total of 1348 subjects ages 18-65 y were recruited in a cross-sectional study that was conducted in 2018-2019 in the northern West Bank. A total of 1082 subjects participated; 51.7% were men. The prevalence of MetS was high (44.9%), and higher among women (46.1%) than men (44.2%) (p<0.001). The prevalence increased significantly with increasing age and body mass index (BMI) in both genders (p<0.001). However, metabolically obese but normal weight individuals (MONW) (8.4%) were also identified, with a slight increase among women (9.4%) compared with men (7.5%) (p=0.56). MetS was more likely to be prevalent among participants with increased fasting blood sugar (5.8 times), increased triglyceride (7.4 times), increased blood pressure (4.5 times) and BMI ≥25 (19.9 times) (p<0.001). The prevalence of MetS was higher among rural (50.3%) vs urban (39.3%) residents and refugees (33.8%). With increasing age and obesity, clustering of MetS components increased remarkably in both genders. Effective prevention and treatment strategies for MetS and its risk factors should be developed targeting different ages and genders.


Biochemical characterization of blood plasma of coronary artery disease patients by in vitro high-resolution proton NMR spectroscopy.
This study aimed to investigate the biochemical profile of blood plasma of patients with coronary artery disease (CAD) and angiographically normal subjects (controls) to determine biomarkers for their differentiation. In this double blind study, 5 mL venous blood was drawn before angiography from CAD patients (n=60) and controls (n=13) comprising angiography normal individuals. In vitro high-resolution NMR spectroscopy of these blood plasma samples was carried out at 400 MHz, and intensity data were analysed with partial least square discriminant analysis. Categorization of subjects as controls or CAD patients and the patients further as single vessel disease (SVD), double vessel disease (DVD) and triple vessel disease (TVD) was done at the end of the study based on their angiography reports. Raised levels of lipids, alanine (Ala) and isoleucine/leucine/valine (Ile/Leu/Val) were observed in CAD patients compared with controls. Partial least square discriminant analysis showed separation between controls vs CAD patients. TVD patients showed increased levels of Ile/Leu/Val and Ala compared with controls and SVD. Alanine, Ile/Leu/Val, and LDL/VLDL appear as possible biomarkers for distinguishing between controls and patients with SVD and TVD. A metabolic adaptation of myocardium may play a role in raising the Ala level.


Effect of dietary protein or calcium supplement on the expression of collagen I and dentine phosphoprotein of rats with dental fluorosis.
This study aims to assess the roles of dietary protein (Pr) and calcium (Ca) levels associated with excessive fluoride (F) intake and the impact of Pr, Ca, and F on expression of collagen I (COL I) and dentine phosphoprotein (DPP) in rat incisors. Seventy-two rats were randomly allotted to six groups (NC, NC + F, LPrLCa, LPrLCa + F, HPrLCa + F and LPrHCa + F). F, Pr, and Ca were orally administrated to rats for 120 days. The genes and proteins expression levels were quantified. We found that levels of COL1A1 and DSPP gene were respectively decreased by 41.9% and 43.1% in the NC + F group compared with NC group, were respectively decreased by 47.9% and 40.8% in the LPrLCa + F group compared with LPrLCa group, were respectively increased by 71.8% and 39.5% in the HPrLCa + F group and increased by 26.5% and 21.1% in the LPrHCa + F group compared with LPrLCa + F group. Meanwhile, the proteins' expression display with the genes' expression changes were consistent. This study demonstrated that the gene and protein expressions of COL I and DPP were reduced by F both in normal nutrition and malnutrition, and it was reversed by Pr and Ca supplementation, with the effect of Pr being greater than that of Ca.


Role of non-invasive imaging in the management of coronary artery disease: an assessment of likely change over the next 10 years. A report from the British Cardiovascular Society Working Group.
Coronary angiography has been the gold standard for determining the severity, extent and prognosis of coronary atheromatous disease for the past 15-20 years. However, established non-invasive testing (such as myocardial perfusion scintigraphy and stress echocardiography) and newer imaging modalities (multi-detector x ray computed tomography and cardiovascular magnetic resonance) now need to be considered increasingly as a challenge to coronary angiography in contemporary practice. An important consideration is the degree to which appropriate use of such techniques impacts on the need for coronary angiography over the next 10-15 years. This review aims to determine the role of the various investigation techniques in the management of coronary artery disease and their resource implications, and should help determine future service provision, accepting that we are in a period of significant technological change.


Disparity and convergence in bipedal archosaur locomotion.
This study aims to investigate functional disparity in the locomotor apparatus of bipedal archosaurs. We use reconstructions of hindlimb myology of extant and extinct archosaurs to generate musculoskeletal biomechanical models to test hypothesized convergence between bipedal crocodile-line archosaurs and dinosaurs. Quantitative comparison of muscle leverage supports the inference that bipedal crocodile-line archosaurs and non-avian theropods had highly convergent hindlimb myology, suggesting similar muscular mechanics and neuromuscular control of locomotion. While these groups independently evolved similar musculoskeletal solutions to the challenges of parasagittally erect bipedalism, differences also clearly exist, particularly the distinct hip and crurotarsal ankle morphology characteristic of many pseudosuchian archosaurs. Furthermore, comparative analyses of muscle design in extant archosaurs reveal that muscular parameters such as size and architecture are more highly adapted or optimized for habitual locomotion than moment arms. The importance of these aspects of muscle design, which are not directly retrievable from fossils, warns against over-extrapolating the functional significance of anatomical convergences. Nevertheless, links identified between posture, muscle moments and neural control in archosaur locomotion suggest that functional interpretations of osteological changes in limb anatomy traditionally linked to postural evolution in Late Triassic archosaurs could be constrained through musculoskeletal modelling.


The use of micro-CT to evaluate cortical bone geometry and strength in nude rats: correlation with mechanical testing, pQCT and DXA.
In both clinical and experimental settings, access to quantitative methods enabling the objective evaluation of cortical bone mass, structure, geometry and strength are essential for the assessment of efficacy and safety of different treatments aimed to improve bone strength. The ability of non-invasive methodologies (DXA, pQCT and micro-CT) to assess and quantify cortical bone mass and geometry was tested in a nude rat model in which bone loss was induced by surgical castration. Treatment with a bone antiresorptive (alendronate) or a bone forming (PTH) drug was used to: (A) validate the nude rat model in terms of bone metabolism, (B) test the ability of each technology to detect change in cortical bone geometry and (C) correlate cortical bone geometry with bone strength data obtained by 3-point bending method. Our observations regarding effect of castration and treatment with PTH and alendronate on cortical bone parameters in nude rats is in general agreement with previously published data obtained in immunocompetent male rats under similar experimental conditions. Data presented here support the hypothesis that nude rats have similar bone physiology and response to known bone therapies to that observed in normal rats and therefore could be effectively used to predict skeletal response in humans. All three technologies deployed in this study (DXA, pQCT and micro-CT) proved useful in describing cancellous and/or cortical bone parameters and positive correlations were demonstrated between data obtained by different methods. The cross-sectional area of a bone structure is crucial for resisting loads in bending or torsion and is described as "areal moment of inertia" for bending, and as "polar moment of inertia" in torsion. Novel, three-dimensional micro-CT methodology used in this study to assess geometry of cortical bone provides data that accurately describes cortical bone geometry and parallels cortical bone strength results obtained by the 3-point bending method. Our micro-CT data meet the criteria of providing quick, reproducible and accurate answers regarding cortical bone geometry as a predictor of cortical bone strength.


Perspectives of pharmacy students in Qatar toward interprofessional education and collaborative practice: a mixed methods study.
In an IPE environment, students are expected to have better understanding of the roles, responsibilities, and contribution of other health care professions to enhance interprofessional working and collaboration with an end result of improving patient-centred and team-based care. Although many studies have investigated students' attitudes, very few employ a mixed methods design and hardly are from Middle Eastern countries. A two-staged sequential explanatory mixed method design was used to comprehensively capture the perspectives of pharmacy students toward IPE and collaborative practice. A quantitative survey was conducted as the first stage of the study, followed by an in-depth discussion of these perspectives through a qualitative phase by conducting two focus groups. For the quantitative surveys, the overall response rate was 102/132 (77%) for pharmacy students in Qatar. This was followed by two focus groups with a total of 27 participants from senior and junior students. In exploring the qualitative data, three main themes were identified in relation to the pharmacy students' perspectives. These were on the pharmacy students' perception on the enablers (professional related benefits, patient-related benefits and current positive influences), barriers (previous IPE experiences, educational related issues and current working practices and processes), and recommendations to implementing IPE and collaborative practice (future IPE and pharmacy profession).Overall, the results demonstrate a strong readiness and positive perception by pharmacy students toward IPE and collaborative practice. This study has highlighted different dimensions in pharmacy students' perceptions. It also provided a useful insight into the readiness of pharmacy students in a Middle Eastern university. Students are seeking more IPE experiences formally incorporated into their curriculum and hence educators should capitalise on these positive and enthusiastic attitudes to identify the most effective means for delivering IPE and inform curricula planning. Collaborative practice-ready graduates will produce better-educated professionals delivering higher quality care.


First Report of Cucumber mosaic virus Infecting Watermelon in Serbia.
In June 2012, field-grown watermelon plants (Citrullus lanatus L.) with virus-like symptoms were observed in Silbaš locality, South Backa District of Serbia. Plants infected early in the growing season showed severe symptoms including stunting, mosaic, mottling, blistering, and leaf curling with reduced leaf size, while those infected at later stages exhibited only a mild mosaic. Affected plants were spread across the field and disease incidence was estimated at 40%. Thirteen symptomatic watermelon plants were sampled and analyzed by double-antibody sandwich (DAS)-ELISA using a commercial diagnostic kit (Bioreba AG, Reinach, Switzerland) against the most important watermelon viruses: Cucumber mosaic virus (CMV), Watermelon mosaic virus (WMV), Zucchini yellow mosaic virus (ZYMV), Papaya ringspot virus (PRSV), and Squash mosaic virus (SqMV) (1). Commercial positive and negative controls and an extract from healthy watermelon tissue were included in each ELISA. Serological analyses showed that all plants were positive for CMV and negative for ZYMV, WMV, PRSV, and SqMV. The virus was mechanically transmitted from an ELISA-positive sample (449-12) to five plants of each Citrullus lanatus 'Creamson sweet' and Chenopodium amaranticolor using 0.01 M phosphate buffer (pH 7) with Serbian CMV isolate from Cucurbita pepo 'Olinka' (GenBank Accession No. HM065510) and healthy watermelon plants as positive and negative controls, respectively. Small necrotic lesions on C. amaranticolor and mild mosaic with dark green vein banding on watermelon leaves were observed on all inoculated plants 5 and 14 days post-inoculation, respectively. For further confirmation of CMV infection, reverse transcription (RT)-PCR was performed with the One-Step RT-PCR Kit (Qiagen, Hilden, Germany) using specific primers CMVCPfwd (5'-TGCTTCTCCRCGARWTTGCGT-3') and CMVCPrev (5'-CGTAGCTGGATGGACAACCCG-3'), designed to amplify an 871-bp fragment of the RNA3 including the whole CP gene. Total RNA from 12 naturally infected and five mechanically infected watermelon plants was extracted with the RNease Plant Mini Kit (Qiagen). Total RNA obtained from the Serbian CMV isolate (HM065510) and healthy watermelon plants were used as positive and negative controls, respectively. The expected size of RT-PCR products were amplified from all naturally and mechanically infected watermelon plants but not from healthy tissues. The PCR product derived from isolate 449-12 was purified and directly sequenced using the same primer pair as in RT-PCR (JX280942) and analyzed by MEGA5 software (3). Sequence comparison of the complete CP gene (657 nt) revealed that the Serbian isolate 449-12 shared the highest nucleotide identity of 98.9% (99.1% amino acid identity) with the Spanish melon isolate (AJ829777) and Syrian tomato isolate (AB448696). To our knowledge, this is the first report of CMV on watermelon in Serbia. CMV is widely distributed within the Mediterranean basin where it has a substantial impact on many agricultural crops (2) and is often found to be prevalent during pumpkin and squash surveys in Serbia (4). The presence of CMV on watermelon could therefore represent a serious threat to this valuable crop in Serbia. References: (1) L. M. da Silveira et al. Trop. Plant Pathol. 34:123, 2009. (2) M. Jacquemond. Adv. Virus Res. 84:439, 2012. (3) K. Tamura et al. Mol. Biol. Evol. 28:2731, 2011. (4) A. Vucurovic et al. Eur. J. Plant Pathol. 133:935, 2012.


Multi-scale analysis of schizophrenia risk genes, brain structure, and clinical symptoms reveals integrative clues for subtyping schizophrenia patients.
Analysis linking directly genomics, neuroimaging phenotypes and clinical measurements is crucial for understanding psychiatric disorders, but remains rare. Here, we describe a multi-scale analysis using genome-wide SNPs, gene expression, grey matter volume (GMV), and the positive and negative syndrome scale scores (PANSS) to explore the etiology of schizophrenia. With 72 drug-naive schizophrenic first episode patients (FEPs) and 73 matched heathy controls, we identified 108 genes, from schizophrenia risk genes, that correlated significantly with GMV, which are highly co-expressed in the brain during development. Among these 108 candidates, 19 distinct genes were found associated with 16 brain regions referred to as hot clusters (HCs), primarily in the frontal cortex, sensory-motor regions and temporal and parietal regions. The patients were subtyped into three groups with distinguishable PANSS scores by the GMV of the identified HCs. Furthermore, we found that HCs with common GMV among patient groups are related to genes that mostly mapped to pathways relevant to neural signaling, which are associated with the risk for schizophrenia. Our results provide an integrated view of how genetic variants may affect brain structures that lead to distinct disease phenotypes. The method of multi-scale analysis that was described in this research, may help to advance the understanding of the etiology of schizophrenia.


Can temperature be used to tune the selectivity of membrane ion-selective electrodes?
The selectivity coefficients, KIJpot, of ion-selective electrodes (ISEs) have been fundamentally related to thermodynamic parameters, but yet, the effect of temperature on KIJpot has not been studied. We describe a new approach to fine-tune the selectivity of ISEs based on the effect of temperature on selectivity coefficients. This effect was quantified for ion exchangers as well as neutral carrier ionophores. Potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate was used as an ion exchanger in a poly(vinyl chloride) membrane. The corresponding electrode showed an inverse relationship between log KNa+,K+pot and temperature. Additionally, sodium-selective electrodes using monensin, monensin methyl ester (MME), and monensin decyl ester (MDE) were evaluated as models of electrodes based on neutral carriers. The electrode based on monensin showed an enhancement in the selectivity for sodium over potassium by half an order of magnitude as the temperature increased from 20 to 50 degrees C, while the electrodes based on MME or MDE showed a very small change in selectivity. This can be explained in light of changes in the formation constants between the ions and ionophores with temperature. The theory of the effect of temperature on selectivity for both ion exchangers and neutral carrier ionophores is also discussed.


The analgesic and anti-inflammatory activities of the extract of Albizia lebbeck in animal model.
The extract of the bark of Albizia lebbeck Benth. obtained by cold extraction of mixture of equal proportions of petroleum ether, ethyl acetate and methanol was chosen for pharmacological screening. In rat paw edema model induced by carrageenan, the extract at the 400 mg/kg dose level showed 36.68% (p<0.001) inhibition of edema volume at the end of 4h. In the acetic acid-induced writhing test, the extract at the 200 and 400 mg/kg dose level showed 39.9% and 52.4 % inhibition of writhing, respectively. In radiant heat tail-flick method the crude extract produced 40.74% (p<0.001) and 61.48% (p<0.001) elongation of tail flicking time 30 minutes after oral administration at the 200 and 400 mg/kg dose level, respectively.


Competition Between Transients in the Rate of Approach to a Fixed Point.
The goal of this paper is to provide and apply tools for analyzing a specific aspect of transient dynamics not covered by previous theory. The question we address is whether one component of a perturbed solution to a system of differential equations can overtake the corresponding component of a reference solution as both converge to a stable node at the origin, given that the perturbed solution was initially farther away and that both solutions are nonnegative for all time. We call this phenomenon tolerance, for its relation to a biological effect. We show using geometric arguments that tolerance will exist in generic linear systems with a complete set of eigenvectors and in excitable nonlinear systems. We also define a notion of inhibition that may constrain the regions in phase space where the possibility of tolerance arises in general systems. However, these general existence theorems do not not yield an assessment of tolerance for specific initial conditions. To address that issue, we develop some analytical tools for determining if particular perturbed and reference solution initial conditions will exhibit tolerance.


Ultrasound image of the skin, apparatus and imaging basics.
Ultrasound imaging of the skin is becoming more and more popular. Skin ultrasound examinations are used both in order to assess healthy skin and to evaluate pathological lesions. They are mainly performed in dermatology as well as in broadly understood aesthetic medicine and cosmetology. At present, skin imaging is enabled by high-frequency equipment and high-quality conventional devices. The introduction of high-frequency electronic transducers which are supported by conventional scanners may be a turning point in skin ultrasound equipment. Irrespective of the ultrasound scanner, three layers may be distinguished in the image of the healthy skin: epidermal echo, dermis and subcutaneous tissue. High-frequency equipment allows for detailed imaging of the epidermal echo, dermis and upper part of the subcutaneous tissue. It is also possible to visualize the skin appendages (hair with follicles and nails) as well as slight vessels that run in the dermis and upper subcutaneous tissue. Contrary to high-frequency equipment, conventional scanners do not allow for a detailed assessment of the epidermal and dermal echoes. Instead, they enable the visualization of the entire subcutaneous tissue. The following parameters are used for the assessment of skin ultrasound images: thickness of individual skin layers, caliber of blood vessels, echogenicity of the dermis or its individual layers, echogenicity of the subcutaneous tissue as well as the presence or absence of flow in slight venous vessels. Currently, the studies on the usage of sonoelastography for skin assessment are in progress. Considering the dynamic development of skin imaging equipment and its diagnostic possibilities, one might suspect that high-frequency examinations will become more common and will be fundamental for the evaluation of both healthy and pathologically altered skin. This paper is an introduction to a series of articles on the clinical application of high-frequency ultrasound. The next articles will be published in the subsequent issues.


Perceived preparedness to provide preventive counseling: reports of graduating primary care residents at academic health centers.
To assess the perceived preparedness of residents in adult primary care specialties to counsel patients about preventive care and psychosocial issues. Cross-sectional national mail survey of residents (63% response rate). Nine hundred twenty-eight final-year primary care residents in Internal Medicine (IM), family practice (FP), and Obstetrics/Gynecology (OB/GYN) at 162 U.S. academic health centers. Residents self-rated preparedness to counsel patients about smoking, diet and exercise, substance abuse, domestic violence, and depression. Residents felt better prepared to counsel about smoking (62%) and diet and exercise (53%) than about depression (37%), substance abuse (36%), or domestic violence (21%). In most areas, females felt better prepared than males. Rates of counseling preparedness varied significantly by specialty after adjustment for gender, race, medical school location, and percent of training spent in ambulatory settings. FP residents felt better prepared than OB/GYN residents to counsel about smoking, diet and exercise, and depression, while OB/GYN residents felt better prepared to address domestic violence than IM or FP residents. IM residents' perceptions of preparedness were between the other 2 specialties. Proportion of training spent in ambulatory settings was not associated with residents' perceived preparedness. Physicians completing residencies in adult primary care did not feel very well prepared to counsel patients about preventive and psychosocial issues. Significant differences exist among specialties, even after adjusting for differences in time spent in ambulatory settings. Increasing residency time in ambulatory settings may not alone be sufficient to ensure that residents emerge with adequate counseling skills.


Psychometric validation of the Family Outcomes Survey-Revised in Japan.
According to a revision of Japan's Basic Law for Persons with Disabilities in 2011, Article 17 stipulated the government's obligation to provide early intervention to children with disabilities. However, the concept of family outcomes in early intervention has not really been considered in Japan yet. This article describes the development and validation of the Japanese version of the Family Outcomes Survey Revised (FOS-R). Our goal was to determine whether this survey for assessing how families of children with disabilities are affected by early intervention would be appropriate for use in early intervention in Japan. Both the Japanese version of the FOS-R and an anonymous, self-administered questionnaire about background factors were given to 394 mothers of children who were either currently using or had in the past year used early intervention at an early intervention facility or medical institution. Survey responses were obtained from 335 mothers (response rate of 85.0%). The total number of subjects in the analysis was 301 mothers who answered the Japanese version of the FOS-R completely. To assess content validity, another survey was given to 115 experts involved in supporting children with disabilities and their families. The family outcomes indicator items as well as the helpfulness indicators items showed good psychometric properties. Although the components of the FOS-R worked better as individual subscales than as a single scale, we confirmed that a total score was also psychometrically valid. We also confirmed both content validity and external validity. The Japanese version of the FOS-R appears to be a valid tool for assessing the benefits experienced by families as a result of services received, but further research is needed to determine the nature of practices most likely to lead to positive family outcomes.


Radiotherapy-induced basal cell carcinomas of the scalp: are they genetically different?
The treatment of tinea capitis using radiotherapy was introduced at the beginning of the twentieth century. In Israel, between 1949 and 1960, approximately 17,000 children underwent radiotherapy treatments for tinea capitis (actual numbers are probably higher due to irradiation in countries of origin as a prerequisite for immigration). Skin cancer presents a major problem for patients who underwent irradiation for the treatment of tinea capitis [aggressive biological behavior, multiple basal cell carcinomas (BCCs), up to 40 lesions in a single patient, with no predisposing condition such as Gorlin's or Bazex's syndromes]. There are ample data in the literature concerning the molecular changes in ultraviolet (UV) radiation-induced BCCs. However, similar data regarding ionizing radiation-induced BCCs are scarce. One work found higher rates of p53 and PTCH (both are tumor suppressor genes whose alterations are associated with BCC formation and frequency, but not biological behavior) abnormalities in post ionizing radiation BCCs. The absence of documented differences in gene expression that would account for a different biological behavior of radiotherapy-related BCCs, coupled with the aggressive and recurrent nature of these lesions, has propelled us to examine these differences by comparing gene expression in BCCs of the scalps of patients who were previously irradiated for tinea capitis in their childhood and of the scalps of patients who were not. Tissue samples of excised scalp BCCs from seven previously irradiated patients (five male, two female) and seven not previously irradiated patients (six male, one female) were frozen upon excision and genetically analyzed using DNA microarray chips. No correlation was found between previous ionizing irradiation and gene expression. The negative results of this study, coupled with the observation of aggressive biological behavior of BCCs in previously irradiated patients merit further attention. Other explanations for the aggressive biological behavior of radiotherapy-induced BCCs come to mind. One such explanation could be that the difference between the groups lies not in the tumor itself, but in the host, who is more susceptible to the local destruction caused by the tumor due to changes in the surrounding tissue (e.g., impaired blood supply due to radiation, structural damage in seemingly healthy skin). This hypothesis will be the focus of further research. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Nonlinear mixed-effects models with misspecified random-effects distribution.
Nonlinear mixed-effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random-effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random-effects distribution in nonlinear mixed-effects models. Our study is focused on Gauss-Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random-effects distribution in nonlinear mixed-effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed-effects parameters in nonlinear mixed-effects models are generally robust to deviations from normality of the random-effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random-effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.


A Telfairia Occidentalis Seed-incorporated Diet May Be Useful in Inhibiting the Induction of Experimental Andropause.
Andropause, a prevalent pathology of men, results from an imbalance in steroid hormone concentrations that often is associated with aging, and reduces the quality of life of the sufferer. This study investigates the usefulness of a diet containing 15% Telfairia occidentalis seeds in the inhibition of the induction of experimental andropause. Twenty male rats were divided into four equal groups. Rats in the test group received dihydrotestosterone and estradiol valerate (ratio 10:1) subcutaneously every other day for 28 days and were placed on the test diet. Those in control I received the hormones, but not the test diet. Rats in controls II and III received olive oil (vehicle) and were placed on the test diet and normal diet, respectively. Testes weights and relative weights, serum testosterone concentrations, and testosterone concentration per gram of testicular tissue were measured or determined in all rats using standard protocols. Data were analyzed and differences between means separated using one-way analysis of variance. Rats in the test group had slightly larger mean relative testes weights compared to those in control I, though both were significantly (P<0.001) smaller than the values obtained in controls II and III, respectively. Rats in the test group had significantly higher (P=0.034) serum testosterone concentrations relative to the control I group 6.9(0.3) ng/ml vs. 4.7(0.1) ng/ml, while the testosterone relative to testes weight values (ng/ml/g) of the test group was 16.8(3.4), and for controls I, II, and III the values were 12.3(1.4), 5.5(0.4), and 4.6(0.7), respectively. The differences between the test and control groups were all significant (P=0.04 in control I, and <0.001 in controls II and III). The test diet resulted in a modest reduction of biochemical castration and an improvement in secretory capacity of the testes of the test rats, relative to the control group that received the hormones but was placed on a normal diet. T. occidentalis seeds-incorporated diet may be useful in inhibiting the induction of experimental andropause.


Improvement in appropriate utilization of recombinant human erythropoietin pre- and post-implementation of a required order form.
Erythropoietin stimulating agents (ESAs) are high-cost medications that have a significant impact on many pharmacy budgets. Recently, ESAs have received stronger safety warnings and reimbursement has been curtailed by third-party payers including the Centers for Medicare and Medicaid Services. For these reasons, many hospitals are developing strategies to optimize their use. A required order form with acceptable indications and dosing was implemented at an academic medical center in an attempt to improve dosing and appropriate utilization of ESAs. To determine whether implementation of a required order form increased appropriate use and/or decreased total utilization of recombinant human erythropoietin (rHuEPO). This was a retrospective cohort study of rHuEPO utilization for 4 months pre- and 6 months post-implementation (April 2008-January 2009). Implementation of a required order form for rHuEPO resulted in significantly fewer patients receiving inappropriate doses of rHuEPO (51.3% vs 19.2%, p < 0.001). The number of patients treated, adjusted to hospital census, was also reduced after implementation of the order form (0.003 vs 0.004 pts./average pt. days, p = 0.03). Annual spending for rHuEPO was reduced by 47% during 2008 despite an increased acquisition cost. Implementation of a required order form with evidence-based dosing recommendations can be an effective strategy to improve appropriate utilization of rHuEPO.


Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy.
Polypharmacy and inappropriate medication use is a problem in elderly patients, who are more likely to experience adverse effects from multiple treatments and less likely to obtain the same therapeutic benefit as younger populations. The Good Palliative-Geriatric Practice algorithm for drug discontinuation has been shown to be effective in reducing polypharmacy and improving mortality and morbidity in nursing home inpatients. This study reports the feasibility of this approach in community-dwelling older patients. The Good Palliative-Geriatric Practice algorithm was applied to a cohort of 70 community-dwelling older patients to recommend drug discontinuations. Success rates of discontinuation, morbidity, mortality, and changes in health status were recorded. The mean (SD) age of the 70 patients was 82.8 (6.9) years. Forty-three patients (61%) had 3 or more and 26% had 5 or more comorbidities. The mean follow-up was 19 months. Participants used a mean (SD) of 7.7 (3.7) medications. Protocol indicated that discontinuation was recommended for 311 medications in 64 patients (58% of drugs; mean [SD], 4.4 [2.5] drugs per patient overall, 4.9 per patient who had discontinuation). Of the discontinued drug therapies, 2% were restarted because of recurrence of the original indication. Taking nonconsent and failures together, successful discontinuation was achieved in 81%. Ten elderly patients (14%) died after a mean follow-up of 13 months, with the mean age at death of 89 years. No significant adverse events or deaths were attributable to discontinuation, and 88% of patients reported global improvement in health. It is feasible to decrease medication burden in community-dwelling elderly patients. This tool would be suitable for larger randomized controlled trials in different clinical settings.


Time-resolved resonance Raman observation of the dimerization of didehydroazepines in solution.
Time-resolved resonance Raman (TR3) studies of the photochemistry of phenyl azide, 3-hyroxyphenyl azide, 3-methoxyphenyl azide and 3-nitrophenyl azide in acetonitrile:water solutions is reported. After photolysis of these four aryl azides in room temperature solutions, only one species was observed in the TR3 spectra for each azide, respectively at the probe wavelengths employed in the TR3 experiments. The species observed after photolysis of 3-nitrophenyl azide was assigned to 3,3'-dinitroazobenzene, an azo compound formed from the dimerization reaction of triplet 3-nitrophenylnitrene. In contrast, the species observed after photolysis of phenyl azide, 3-hydroxyphenyl azide and 3-methoxyphenyl azide were tentatively assigned to intermediates formed from the dimerization of didehydroazepines that are produced from the ring expansion reaction of the respective singlet arylnitrene. To our knowledge, this is the first time-resolved vibrational spectroscopic observation of the dimerization reaction of didehydroazepines in solution. In addition, these are the first resonance Raman spectra reported for dimers formed from didehydroazepines. We briefly discuss the structures, properties and chemical reactivity of the dimer species observed in the TR3 spectra and possible implications for the photochemistry of aryl azides.


A maternally inherited autosomal point mutation in human phospholipase C zeta (PLCζ) leads to male infertility.
Male factor and idiopathic infertility contribute significantly to global infertility, with abnormal testicular gene expression considered to be a major cause. Certain types of male infertility are caused by failure of the sperm to activate the oocyte, a process normally regulated by calcium oscillations, thought to be induced by a sperm-specific phospholipase C, PLCzeta (PLCζ). Previously, we identified a point mutation in an infertile male resulting in the substitution of histidine for proline at position 398 of the protein sequence (PLCζ(H398P)), leading to abnormal PLCζ function and infertility. Here, using a combination of direct-sequencing and mini-sequencing of the PLCζ gene from the patient and his family, we report the identification of a second PLCζ mutation in the same patient resulting in a histidine to leucine substitution at position 233 (PLCζ(H233L)), which is predicted to disrupt local protein interactions in a manner similar to PLCζ(H398P) and was shown to exhibit abnormal calcium oscillatory ability following predictive 3D modelling and cRNA injection in mouse oocytes respectively. We show that PLCζ(H233L) and PLCζ(H398P) exist on distinct parental chromosomes, the former inherited from the patient's mother and the latter from his father. Neither mutation was detected utilizing custom-made single-nucleotide polymorphism assays in 100 fertile males and females, or 8 infertile males with characterized oocyte activation deficiency. Collectively, our findings provide further evidence regarding the importance of PLCζ at oocyte activation and forms of male infertility where this is deficient. Additionally, we show that the inheritance patterns underlying male infertility are more complex than previously thought and may involve maternal mechanisms.


Management of severe maxillary deficiency in childhood and adolescence through distraction osteogenesis with an external, adjustable, rigid distraction device.
We present our technique for maxillary distraction osteogenesis in patients with severe maxillary hypoplasia. With the use of an external, adjustable, rigid distraction device, we can now treat patients with severe maxillary hypoplasia with a precise and controlled distraction process, obtaining predictable results. This technique has allowed us to treat patients in all age groups. In this report we review our indications for maxillary distraction and describe our technique using an external, adjustable, rigid midface distraction device.


MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response.
The p53 inhibitor, MDM4 (MDMX) is a cytoplasmic protein with p53-activating function under DNA damage conditions. Particularly, MDM4 promotes phosphorylation of p53 at Ser46, a modification that precedes different p53 activities. We investigated the mechanism by which MDM4 promotes this p53 modification and its consequences in untransformed mammary epithelial cells and tissues. In response to severe DNA damage, MDM4 stimulates p53Ser46(P) by binding and stabilizing serine-threonine kinase HIPK2. Under these conditions, the p53-inhibitory complex, MDM4/MDM2, dissociates and this allows MDM4 to promote p53/HIPK2 functional interaction. Comparative proteomic analysis of DNA damage-treated cells versus -untreated cells evidenced a diffuse downregulation of proteins with anti-apoptotic activity, some of which were targets of p53Ser46(P)/HIPK2 repressive activity. Importantly, MDM4 depletion abolishes the downregulation of these proteins indicating the requirement of MDM4 to promote p53-mediated transcriptional repression. Consistently, MDM4-mediated HIPK2/p53 activation precedes HIPK2/p53 nuclear translocation and activity. Noteworthy, repression of these proteins was evident also in mammary glands of mice subjected to γ-irradiation and was significantly enhanced in transgenic mice overexpressing MDM4. This study evidences the flexibility of MDM2/MDM4 heterodimer, which allows the development of a positive activity of cytoplasmic MDM4 towards p53-mediated transcriptional function. Noteworthy, this activity uncovers coordinated repression of molecules with shared anti-apoptotic function which precedes active cell apoptosis and that are frequently overexpressed and/or markers of tumour phenotype in human cancer.


Gender bias in scholarly peer review.
Peer review is the cornerstone of scholarly publishing and it is essential that peer reviewers are appointed on the basis of their expertise alone. However, it is difficult to check for any bias in the peer-review process because the identity of peer reviewers generally remains confidential. Here, using public information about the identities of 9000 editors and 43000 reviewers from the Frontiers series of journals, we show that women are underrepresented in the peer-review process, that editors of both genders operate with substantial same-gender preference (homophily), and that the mechanisms of this homophily are gender-dependent. We also show that homophily will persist even if numerical parity between genders is reached, highlighting the need for increased efforts to combat subtler forms of gender bias in scholarly publishing.


Number of days required to measure sedentary time and physical activity using accelerometery in rheumatoid arthritis: a reliability study.
This study aimed to determine the minimum number of days required to reliably estimate free-living sedentary time, light-intensity physical activity (LPA) and moderate-intensity physical activity (MPA) using accelerometer data in people with Rheumatoid Arthritis (RA), according to Disease Activity Score-28-C-reactive protein (DAS-28-CRP). Secondary analysis of two existing RA cohorts with controlled (cohort 1) and active (cohort 2) disease was undertaken. People with RA were classified as being in remission (DAS-28-CRP < 2.4, n = 9), or with low (DAS-28-CRP ≥ 2.4-≤ 3.2, n = 15), moderate (DAS-28-CRP > 3.2-≤ 5.1, n = 41) or high (DAS-28-CRP > 5.1, n = 16) disease activity. Participants wore an ActiGraph accelerometer on their right hip for 7 days during waking hours. Validated RA-specific cut-points were applied to accelerometer data to estimate free-living sedentary time, LPA and MPA (%/day). Single-day intraclass correlation coefficients (ICC) were calculated and used in the Spearman Brown prophecy formula to determine the number of monitoring days required to achieve measurement reliability (ICC ≥ 0.80) for each group. The remission group required ≥ 4 monitoring days to achieve an ICC ≥ 0.80 for sedentary time and LPA, with low, moderate and high disease activity groups requiring ≥ 3 monitoring days to reliably estimate these behaviours. The monitoring days required for MPA were more variable across disease activity groups (remission = ≥ 3 days; low = ≥ 2 days; moderate = ≥ 3 days; high = ≥ 5 days). We conclude at least 4 monitoring days will reliably estimate sedentary time and LPA in RA, across the whole spectrum of disease activity. However, to reliably estimate behaviours across the movement continuum (sedentary time, LPA, MPA), at least 5 monitoring days are required.


The scope and responsibility of medicine.
To engender discussion of what the scope and responsibility of medicine ought to be in today's society, California Medicine printed in its June issue six essays by authors known to have keen if various interest in the subject. In presenting the essays the editors expressed hope that they would be the beginning of a forum from which a definition of our profession's responsibilities may be distilled. Readers were invited to take part in a continuation of the forum in succeeding issues. Following are two contributions selected from those received to date. Others will be published in the months ahead. If you have thoughts on the subject, just address them to the editors of California Medicine, 693 Sutter Street, San Francisco, California 94102. Keep your essays short, please.


Antiobesity effects of Chinese black tea (Pu-erh tea) extract and gallic acid.
The antiobesity effects of Chinese black tea (Pu-erh tea) and of gallic acid (GA) were investigated using in vitro and in vivo assays. Chinese black tea extract (BTE) and GA inhibited pancreatic lipase activity in a dose-dependent manner in vitro; the IC(inhibitory concentration)(50) values were 101.6 and 9.2 µg/mL, respectively. Black tea extract (50, 100 mg/kg body weight (b.w.)) and GA (15, 45 mg/kg b.w.) significantly suppressed the elevation of blood triglyceride after oral administration of a corn oil emulsion (8 mL oil/kg b.w.) to male ddY mice. Moreover, the antiobesity effects of BTE and GA were also evaluated in a mouse model of diet-induced obesity. Female ddY mice were divided into seven groups; normal diet (ND) group, high fat diet (HFD) group, BTE (0.2% and 0.6% of diets) groups, and GA (0.007%, 0.02% and 0.1% of diets) groups; the experimental groups were fed the test diets for 12 weeks. The BTE 0.6% and GA 0.1% groups showed significant suppression of weight gain. The weight of parametrial adipose tissue was strongly correlated with the body weight. These results suggest that GA contributes to the antiobesity effect of BTE as an active constituent by inhibiting pancreatic lipase activity.


Findings from a community education needs assessment to facilitate the integration of genomic medicine into primary care.
To assess the lay public's knowledge of, and beliefs about, genetics and genetic testing to create an educational initiative that promotes acceptance and utilization of genomic medicine in primary health care. A telephone survey of English-speaking adults in Guilford County, North Carolina was conducted in 2006 to identify community members' educational needs regarding genetics and genetic testing. Most respondents recognized the connection between family history and disease risk. A majority did not appear to know about: (1) basic principles of inheritance, (2) laws prohibiting genetic discrimination, and (3) the availability and limitations of genetic tests. About 25% thought that they could not reduce their risk if they have a genetic predisposition for disease. Knowledge level was affected by education, experience, age, and race. If primary care providers use family history as a risk assessment tool, community education programs must address (1) the collection of family health history, (2) legislation regarding genetic nondiscrimination, (3) benefits and limitations of existing genetic tests, and (4) genetic determinism. Programs emphasizing practical, "how to" information can be targeted to individuals likely to collect family history information and address misperceptions about discrimination, testing, and determinism.


Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group.
Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003). Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.


Retinoid pathway and cancer therapeutics.
The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol-binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid x receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with an emphasis on the application of retinoids in cancer treatment and prevention.


Feeding jejunostomy during Whipple is associated with increased morbidity.
Placement of a feeding jejunostomy tube (FJ) is often performed during pancreaticoduodenectomy (PD). Few studies, however, have sought to determine whether such placement affects postoperative outcomes after PD. This is a retrospective analysis of the National Surgical Quality Improvement Program (NSQIP) database to determine the 30-d-postoperative mortality rate, major complication rate, and overall complication rate of jejunostomy tube placement at the time of PD. Univariate and multivariate comparison of postoperative outcomes between patients with and without FJ placement during PD was performed on a total of 4930 patients. Thirty-day-postoperative mortality did not differ between the two groups (4.0% for patients with FJ versus 2.7% without, P = 0.13), whereas overall morbidity (43.3% with FJ versus 34.6% without, P < 0.0001) and serious morbidity (29.5% with FJ versus 22.8% without, P < 0.0001) were significantly higher in patients undergoing FJ placement during PD. The specific complications that occurred more frequently in FJ patients than patients without FJ included deep space surgical site infection, pneumonia, unplanned reintubation, acute renal failure, and sepsis. Although FJ placement during PD is considered to be routine at many institutions, our analysis of data from NSQIP suggest that FJ placement may be associated with increased postoperative morbidity.


Comparing diverse health promotion programs using overall self-rated health as a common metric.
Health promotion programs may target a variety of behaviors including weight loss, exercise, stress, nutrition, or other risk factors. Comparing the outcomes of diverse programs is hampered by the absence of a common metric. Overall self-rated health has been used as a health outcome measure in population studies and in some primary care studies, but its potential use to monitor the outcomes of health programs is unexplored. The purpose of this study was to compare the outcomes of 4 health promotion programs using change in overall self-rated health as a common metric. Program-specific metrics used were weight change, change in minutes of exercise, change in stress management activities, and change in healthy nutrition practices. We found that, although all of our lifestyle interventions positively affected the program-specific metrics, only the weight loss and exercise programs showed improvement in specific metrics correlated with improvements in overall self-rated health.


End-of-Life Care Intensity Among Adolescent and Young Adult Patients With Cancer in Kaiser Permanente Southern California.
Cancer is the leading disease-related cause of death among adolescents and young adults (AYAs), but little is known about the care that AYA patients with cancer receive at the end of life (EOL). To evaluate the intensity of EOL care among AYA patients with cancer. Cross-sectional study of Kaiser Permanente Southern California (KSPC) cancer registry data and electronic health records for 663 AYA patients with either stage I to III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. All patients were treated within KSPC, an integrated health care delivery system, and died between 2001 and 2010 before age 40 years (age range at time of death, 15-39 years). (1) Chemotherapy use in the last 14 days of life; (2) intensive care unit (ICU) care in the last 30 days of life; (3) more than 1 emergency department (ED) visit in the last 30 days of life; (4) hospitalization in the last 30 days of life; and (5) a composite measure of medically intensive EOL care including any of the aforementioned measures. Eleven percent of patients (72 of 663) received chemotherapy within 14 days of death. In the last 30 days of life, 22% of patients (144 of 663) were admitted to the ICU; 22% (147 of 663) had more than 1 ED visit; and 62% (413 of 663) were hospitalized. Overall, 68% of patients (449 of 663) received at least 1 medically intensive EOL care measure. Most AYA patients received at least 1 form of medically intensive EOL care. These findings suggest the need to better understand EOL care preferences and decision making in this young population.


Purification and characterization of VanR and the cytosolic domain of VanS: a two-component regulatory system required for vancomycin resistance in Enterococcus faecium BM4147.
Resistance to the glycopeptide antibiotic vancomycin requires five genes. Two of these, vanR and vanS, have sequence homology to cytoplasmic response regulatory (VanR) and transmembrane sensory (VanS) proteins of two-component regulatory systems used to sense and transduce environmental signals. We report the overproduction and purification to homogeneity of VanR (27 kDa) and of a fusion protein of VanS (residues 95-374, the cytosolic domain) to the maltose binding protein (MBP), yielding a MBP-VanS protein of 76 kDa. The MBP-VanS fusion protein displayed an ATP-dependent autophosphorylation on a histidine residue with a rate of 0.17 min-1 and a phosphorylation stoichiometry of 10-15%. 32P-PhosphoMBP-VanS transferred the phosphoryl group to VanR. 32P-Phospho VanR showed chemical stability anticipated for an aspartyl phosphate and was relatively stable to hydrolysis (t1/2 = 10-12 h). Thus, the vancomycin resistance operon appears to have collected and specifically tailored the His kinase and Asp phosphoryl receptor of two-component signal transduction logic for sensing extracellular vancomycin and turning on structural genes, vanA and vanH, to make altered peptidoglycan structures such that vancomycin does not bind.


Identification of regulatory regions of bidirectional genes in cervical cancer.
Bidirectional promoters are shared promoter sequences between divergent gene pair (genes proximal to each other on opposite strands), and can regulate the genes in both directions. In the human genome, > 10% of protein-coding genes are arranged head-to-head on opposite strands, with transcription start sites that are separated by < 1,000 base pairs. Many transcription factor binding sites occur in the bidirectional promoters that influence the expression of 2 opposite genes. Recently, RNA polymerase II (RPol II) ChIP-seq data are used to identify the promoters of coding genes and non-coding RNAs. However, a bidirectional promoter with RPol II ChIP-Seq data has not been found. In some bidirectional promoter regions, the RPol II forms a bi-peak shape, which indicates that 2 promoters are located in the bidirectional region. We have developed a computational approach to identify the regulatory regions of all divergent gene pairs using genome-wide RPol II binding patterns derived from ChIP-seq data, based upon the assumption that the distribution of RPol II binding patterns around the bidirectional promoters are accumulated by RPol II binding of 2 promoters. In HeLa S3 cells, 249 promoter pairs and 1094 single promoters were identified, of which 76 promoters cover only positive genes, 86 promoters cover only negative genes, and 932 promoters cover 2 genes. Gene expression levels and STAT1 binding sites for different promoter categories were therefore examined. The regulatory region of bidirectional promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription. From gene expression and transcription factor binding site analysis, the promoters in bidirectional regions may regulate the closest gene, and STAT1 is involved in primary promoter.


Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a Consensus Statement from the Quantitative Cardiovascular Imaging Study Group.
The detection and characterization of coronary artery stenosis and atherosclerosis using imaging tools are key for clinical decision-making in patients with known or suspected coronary artery disease. In this regard, imaging-based quantification can be improved by choosing the most appropriate imaging modality for diagnosis, treatment and procedural planning. In this Consensus Statement, we provide clinical consensus recommendations on the optimal use of different imaging techniques in various patient populations and describe the advances in imaging technology. Clinical consensus recommendations on the appropriateness of each imaging technique for direct coronary artery visualization were derived through a three-step, real-time Delphi process that took place before, during and after the Second International Quantitative Cardiovascular Imaging Meeting in September 2022. According to the Delphi survey answers, CT is the method of choice to rule out obstructive stenosis in patients with an intermediate pre-test probability of coronary artery disease and enables quantitative assessment of coronary plaque with respect to dimensions, composition, location and related risk of future cardiovascular events, whereas MRI facilitates the visualization of coronary plaque and can be used in experienced centres as a radiation-free, second-line option for non-invasive coronary angiography. PET has the greatest potential for quantifying inflammation in coronary plaque but SPECT currently has a limited role in clinical coronary artery stenosis and atherosclerosis imaging. Invasive coronary angiography is the reference standard for stenosis assessment but cannot characterize coronary plaques. Finally, intravascular ultrasonography and optical coherence tomography are the most important invasive imaging modalities for the identification of plaques at high risk of rupture. The recommendations made in this Consensus Statement will help clinicians to choose the most appropriate imaging modality on the basis of the specific clinical scenario, individual patient characteristics and the availability of each imaging modality.


Acceptability of woman-delivered HIV self-testing to the male partner, and additional interventions: a qualitative study of antenatal care participants in Malawi.
In the era of ambitious HIV targets, novel HIV testing models are required for hard-to-reach groups such as men, who remain underserved by existing services. Pregnancy presents a unique opportunity for partners to test for HIV, as many pregnant women will attend antenatal care (ANC). We describe the views of pregnant women and their male partners on HIV self-test kits that are woman-delivered, alone or with an additional intervention. A formative qualitative study to inform the design of a multi-arm multi-stage cluster-randomized trial, comprised of six focus group discussions and 20 in-depth interviews, was conducted. ANC attendees were purposively sampled on the day of initial clinic visit, while men were recruited after obtaining their contact information from their female partners. Data were analysed using content analysis, and our interpretation is hypothetical as participants were not offered self-test kits. Providing HIV self-test kits to pregnant women to deliver to their male partners was highly acceptable to both women and men. Men preferred this approach compared with standard facility-based testing, as self-testing fits into their lifestyles which were characterized by extreme day-to-day economic pressures, including the need to raise money for food for their household daily. Men and women emphasized the need for careful communication before and after collection of the self-test kits in order to minimize the potential for intimate partner violence although physical violence was perceived as less likely to occur. Most men stated a preference to first self-test alone, followed by testing as a couple. Regarding interventions for optimizing linkage following self-testing, both men and women felt that a fixed financial incentive of approximately USD$2 would increase linkage. However, there were concerns that financial incentives of greater value may lead to multiple pregnancies and lack of child spacing. In this low-income setting, a lottery incentive was considered overly disappointing for those who receive nothing. Phone call reminders were preferred to short messaging service. Woman-delivered HIV self-testing through ANC was acceptable to pregnant women and their male partners. Feedback on additional linkage enablers will be used to alter pre-planned trial arms.


Regulation of tumorigenesis and metastasis of hepatocellular carcinoma tumor endothelial cells by microRNA-3178 and underlying mechanism.
This study explored the effects of microRNA-3178 (miR-3178) on hepatocellular carcinoma (HCC) tumor endothelial cells (TECs) and on the target mRNA. Real-time polymerase chain reaction (PCR) was performed to detect the differential expression of miR-3178 in hepatic sinusoidal endothelial cells (HSECs) and HCC TECs. Furthermore, HCC TECs were transfected with miR-3178 mimic/inhibitor or their respective negative controls. The expression of miR-3178 before and after transfection was confirmed through RT-PCR. The effects of miR-3178 on the proliferation, apoptosis, cell cycle, invasion, migration, and angiogenesis of HCC TECs were also investigated through methyl thiazol tetrazolium assay, flow cytometry, matrigel invasion assay, transwell migration assay, and tube formation assay. Early growth responsive gene 3 (EGR3), as the putative target of miR-3178, was detected through RT-PCR and Western blot. Compared with HSECs, HCC TECs had lower miR-3178 expression levels (P < 0.001). MiR-3178 mimic inhibited proliferation, arrested cell cycle in G1 phase, and increased apoptosis. The numbers of migrated and invaded cells and capillary-like structures were significantly less in the mimic group than in the other groups. MiR-3178 mimic significantly decreased the mRNA and protein expression levels of EGR3. By contrast, miR-3178 inhibitor induced opposite effects. We conclude that miR-3178 was lowly expressed in HCC TECs, and miR-3178 mimic specifically inhibited the proliferation, migration, invasion, and angiogenesis and promoted the apoptosis and G1 phase arrest of HCC TECs in vitro through the inhibition of EGR3 expression. Thus, miR-3178 might be a critical target in HCC therapy.


Strain-Dependent Transcriptome Signatures for Robustness in Lactococcus lactis.
Recently, we demonstrated that fermentation conditions have a strong impact on subsequent survival of Lactococcus lactis strain MG1363 during heat and oxidative stress, two important parameters during spray drying. Moreover, employment of a transcriptome-phenotype matching approach revealed groups of genes associated with robustness towards heat and/or oxidative stress. To investigate if other strains have similar or distinct transcriptome signatures for robustness, we applied an identical transcriptome-robustness phenotype matching approach on the L. lactis strains IL1403, KF147 and SK11, which have previously been demonstrated to display highly diverse robustness phenotypes. These strains were subjected to an identical fermentation regime as was performed earlier for strain MG1363 and consisted of twelve conditions, varying in the level of salt and/or oxygen, as well as fermentation temperature and pH. In the exponential phase of growth, cells were harvested for transcriptome analysis and assessment of heat and oxidative stress survival phenotypes. The variation in fermentation conditions resulted in differences in heat and oxidative stress survival of up to five 10-log units. Effects of the fermentation conditions on stress survival of the L. lactis strains were typically strain-dependent, although the fermentation conditions had mainly similar effects on the growth characteristics of the different strains. By association of the transcriptomes and robustness phenotypes highly strain-specific transcriptome signatures for robustness towards heat and oxidative stress were identified, indicating that multiple mechanisms exist to increase robustness and, as a consequence, robustness of each strain requires individual optimization. However, a relatively small overlap in the transcriptome responses of the strains was also identified and this generic transcriptome signature included genes previously associated with stress (ctsR and lplL) and novel genes, including nanE and genes encoding transport proteins. The transcript levels of these genes can function as indicators of robustness and could aid in selection of fermentation parameters, potentially resulting in more optimal robustness during spray drying.


Content comparison of quality of life questionnaires used in head and neck cancer based on the international classification of functioning, disability and health: a systematic review.
The objective of this study is to provide a content comparison of frequently used questionnaires that assess health-related quality of life (hrQOL) in head and neck cancer (HNC) survivors. This systematic content comparison describes which specific areas of hr-QOL research are covered by each questionnaire. Thereby, it shall assist the clinician in the decision process of instrument selection depending on the content of the study question. As a reference, we chose the international classification of functioning, disability and health (ICF), which was adopted by the WHO in 2001. A systematic literature review identified current hrQOL questionnaires relevant for HNC. The concepts of functioning contained in each questionnaire were translated (linked") to the ICF according to standardized guidelines. Nine questionnaires were selected for further analyses: EORTC-QLQ (C30 + HN35), FACT (G + HN), UW_QOL, QOL-RTI, HN-QOL, PSS-HN, VHI, LORQ, XQ. Within the selected questionnaires, there are 474 concepts, matching 74 second-level ICF categories. The results are presented in tables, showing for each of the validated questionnaires, which of these 74 categories of functioning are addressed. In terms of diversification of content among the questionnaires, there are just eight categories that are used rather frequently and apply to at least five (out of nine) of the questionnaires: e110 Products for personal consumption (i.e., food, drugs), b510 ingestion function, b152 emotional function, b280 sensation of pain, b310 voice, d550 eating, b130 energy and drive function and d850 employment. This ICF-based content comparison provides detailed information on the content that is covered in each questionnaire and thereby assists questionnaire selection. The results question the assumption that HNC-specific questionnaires generally cover the same content. Depending on the study question, the population to be studied and the intervention, there is no unique ideal questionnaire. Compared with other types of qualitative review, the most important advantage of content comparison based on the ICF is the use of an external and independent reference.


[Chronic pelvic pain syndrome: neurostimulation, neuromodulation and acupuncture].
Chronic pelvic pain syndrome (CPPS) is defined by the European Association of Urology guidelines as a non-malignant pain perceived in structures related to the pelvis of either women or men for at least 6 months without proven infection or other obvious pathology. It affects the quality of life of millions of people worldwide and has an impact similar to that reported for other chronic diseases, such as diabetes mellitus, Crohn's disease and congestive heart failure. The treatment of CPPS remains a challenge despite several established first line therapies because many patients are therapy refractory. Unconventional treatments, such as neurostimulation, neuromodulation and acupuncture may be highly successful for treating CPPS and have a favorable adverse event profile. Thus, these promising therapeutic alternatives should be considered more often in daily clinical practice.


Total fluoride intake in children aged 22-35 months in four Colombian cities.
To obtain information on the level of total fluoride intake from food, beverages and toothpaste by children at the age of 22-25 months of low and high socioeconomic status (SES) in major Colombian cities. Daily fluoride intake was assessed by the duplicate plate method and by recovered toothpaste solution during a 3-day period and afterwards analysed by the microdiffusion method. Mean daily fluoride intake was 0.11 (+/-0.10), 0.14 (+/-0.12), 0.10 (+/-0.07) and 0.07 (+/-0.06) mg/kg body weight (bw)/day in Bogota, Medellin, Manizales and Cartagena, respectively. The total fluoride intake was higher in low-SES subjects in the cities of Medellin and Bogota. In the high-SES children of the four cities, the average intakes ranged from 0.06 to 0.09 mg F/kg bw, whereas, the low-SES children in three cities had intakes between 0.11 and 0.21 mg F/kg bw (Cartagena, 0.07). Toothpaste (containing 1000-1500 ppm F, with 1500 ppm F being more common) accounted for approximately 70% of total fluoride intake, followed by food (24%) and beverages (<6%). More than half the children had their teeth brushed by an adult, on average twice a day, using 0.22-0.65 g of toothpaste. Children from three Colombian cities have a mean total daily fluoride intake above the 'optimal range'. Health authorities should promote an appropriate use of fluoridated dentifrices discouraging the use of dentifrices containing 1500 ppm F in children younger than 6 years of age and promoting a campaign of education of parents and oral health professionals on adequate toothbrushing practices.


Rethinking eliminative connectionism.
Humans routinely generalize universal relationships to unfamiliar instances. If we are told "if glork then frum," and "glork," we can infer "frum"; any name that serves as the subject of a sentence can appear as the object of a sentence. These universals are pervasive in language and reasoning. One account of how they are generalized holds that humans possess mechanisms that manipulate symbols and variables; an alternative account holds that symbol-manipulation can be eliminated from scientific theories in favor of descriptions couched in terms of networks of interconnected nodes. Can these "eliminative" connectionist models offer a genuine alternative? This article shows that eliminative connectionist models cannot account for how we extend universals to arbitrary items. The argument runs as follows. First, if these models, as currently conceived, were to extend universals to arbitrary instances, they would have to generalize outside the space of training examples. Next, it is shown that the class of eliminative connectionist models that is currently popular cannot learn to extend universals outside the training space. This limitation might be avoided through the use of an architecture that implements symbol manipulation.


Reevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach.
Depressive severity is typically measured according to total scores on questionnaires that include a diverse range of symptoms despite convincing evidence that depression is not a unitary construct. When evaluated according to aggregate measurements, treatment efficacy is generally modest and differences in efficacy between antidepressant therapies are small. To determine the efficacy of antidepressant treatments on empirically defined groups of symptoms and examine the replicability of these groups. Patient-reported data on patients with depression from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (n = 4039) were used to identify clusters of symptoms in a depressive symptom checklist. The findings were then replicated using the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n = 640). Mixed-effects regression analysis was then performed to determine whether observed symptom clusters have differential response trajectories using intent-to-treat data from both trials (n = 4706) along with 7 additional placebo and active-comparator phase 3 trials of duloxetine (n = 2515). Finally, outcomes for each cluster were estimated separately using machine-learning approaches. The study was conducted from October 28, 2014, to May 19, 2016. Twelve items from the self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) scale and 14 items from the clinician-rated Hamilton Depression (HAM-D) rating scale. Higher scores on the measures indicate greater severity of the symptoms. Of the 4706 patients included in the first analysis, 1722 (36.6%) were male; mean (SD) age was 41.2 (13.3) years. Of the 2515 patients included in the second analysis, 855 (34.0%) were male; mean age was 42.65 (12.17) years. Three symptom clusters in the QIDS-SR scale were identified at baseline in STAR*D. This 3-cluster solution was replicated in CO-MED and was similar for the HAM-D scale. Antidepressants in general (8 of 9 treatments) were more effective for core emotional symptoms than for sleep or atypical symptoms. Differences in efficacy between drugs were often greater than the difference in efficacy between treatments and placebo. For example, high-dose duloxetine outperformed escitalopram in treating core emotional symptoms (effect size, 2.3 HAM-D points during 8 weeks, 95% CI, 1.6 to 3.1; P < .001), but escitalopram was not significantly different from placebo (effect size, 0.03 HAM-D points; 95% CI, -0.7 to 0.8; P = .94). Two common checklists used to measure depressive severity can produce statistically reliable clusters of symptoms. These clusters differ in their responsiveness to treatment both within and across different antidepressant medications. Selecting the best drug for a given cluster may have a bigger benefit than that gained by use of an active compound vs a placebo.


Multimodality Imaging Assessment of Prosthetic Heart Valves.
Echocardiography and fluoroscopy are the main techniques for prosthetic heart valve (PHV) evaluation, but because of specific limitations they may not identify the morphological substrate or the extent of PHV pathology. Cardiac computed tomography (CT) and magnetic resonance imaging (MRI) have emerged as new potential imaging modalities for valve prostheses. We present an overview of the possibilities and pitfalls of CT and MRI for PHV assessment based on a systematic literature review of all experimental and patient studies. For this, a comprehensive systematic search was performed in PubMed and Embase on March 24, 2015, containing CT/MRI and PHV synonyms. Our final selection yielded 82 articles on surgical valves. CT allowed adequate assessment of most modern PHVs and complemented echocardiography in detecting the obstruction cause (pannus or thrombus), bioprosthesis calcifications, and endocarditis extent (valve dehiscence and pseudoaneurysms). No clear advantage over echocardiography was found for the detection of vegetations or periprosthetic regurgitation. Whereas MRI metal artifacts may preclude direct prosthesis analysis, MRI provided information on PHV-related flow patterns and velocities. MRI demonstrated abnormal asymmetrical flow patterns in PHV obstruction and allowed prosthetic regurgitation assessment. Hence, CT shows great clinical relevance as a complementary imaging tool for the diagnostic work-up of patients with suspected PHV obstruction and endocarditis. MRI shows potential for functional PHV assessment although more studies are required to provide diagnostic reference values to allow discrimination of normal from pathological conditions.


Hepatocytes in the bile duct-ligated rat express Bcl-2.
Hepatocytes do not express Bcl-2, a repressor of apoptosis. In contrast, cholangiocytes, which are in direct contact with bile, do express Bcl-2. Because cholestasis results in the retention of bile within hepatocytes, we reasoned cholestasis may induce hepatocellular expression of Bcl-2. Thus our aim was to determine whether hepatocytes express Bcl-2 or alter expression of other Bcl-2 family members in cholestasis using the bile duct-ligated (BDL) rat as a model of cholestasis. De novo Bcl-2 expression was observed in hepatocytes of BDL rats assessed by reverse transcriptase-polymerase chain reaction and immunoblot analysis. Immunohistochemistry demonstrated that Bcl-2 expression in hepatocytes was greater in periportal hepatocytes than pericentral hepatocytes. Expression of Bcl-x (an antiapoptotic Bcl-2 family protein) was not altered by bile duct ligation, whereas expression of Bax (a proapoptotic Bcl-2 family protein) increased slightly as determined by Northern and Western blot analyses. Bcl-2-positive hepatocytes isolated from BDL rats were resistant to induction of apoptosis by 50 microM glycochenodeoxycholate. Our results demonstrate, for the first time, expression of Bcl-2 by hepatocytes during cholestasis. We suggest that hepatocellular expression of Bcl-2 during cholestasis is an adaptive phenomenon to resist apoptosis by toxic bile salts.


A combined crossed molecular beams and computational study on the formation of distinct resonantly stabilized C5H3 radicals via chemically activated C5H4 and C6H6 intermediates.
The crossed molecular beams technique was utilized to explore the formation of three isomers of resonantly stabilized (C5H3) radicals along with their d2-substituted counterparts via the bimolecular reactions of singlet/triplet dicarbon [C2(X1Σ+g/a3Πu)] with methylacetylene [CH3CCH(X1A1)], d3-methylacetylene [CD3CCH(X1A1)], and 1-butyne [C2H5CCH(X1A')] at collision energies up to 26 kJ mol-1via chemically activated singlet/triplet C5H4/C5D3H and C6H6 intermediates. These studies exploit a newly developed supersonic dicarbon [C2(X1Σ+g/a3Πu)] beam generated via photolysis of tetrachloroethylene [C2Cl4(X1Ag)] by excluding interference from carbon atoms, which represent the dominating (interfering) species in ablation-based dicarbon sources. We evaluated the performance of the dicarbon [C2(X1Σ+g/a3Πu)] beam in reactions with methylacetylene [CH3CCH(X1A1)] and d3-methylacetylene [CD3CCH(X1A1)]; the investigations demonstrate that the reaction dynamics match previous studies in our laboratory utilizing ablation-based dicarbon sources involving the synthesis of 1,4-pentadiynyl-3 [HCCCHCCH(X2B1)] and 2,4-pentadiynyl-1 [H2CCCCCH(X2B1)] radicals via hydrogen (deuterium) atom elimination. Considering the C2(X1Σ+g/a3Πu)-1-butyne [C2H5CCH(X1A')] reaction, the hitherto elusive methyl-loss pathway was detected. This channel forms the previously unknown resonantly stabilized penta-1-yn-3,4-dienyl-1 [H2CCCHCC(X2A)] radical along with the methyl radical [CH3(X2A2'')] and is open exclusively on the triplet surface with an overall reaction energy of -86 ± 10 kJ mol-1. The preferred reaction pathways proceed first by barrierless addition of triplet dicarbon to the π-electronic system of 1-butyne, either to both acetylenic carbon atoms or to the sterically more accessible carbon atom, to form the methyl-bearing triplet C6H6 intermediates [i41b] and [i81b], respectively, with the latter decomposing via a tight exit transition state to penta-1-yn-3,4-dienyl-1 [(H2CCCHCC(X2A)] plus the methyl radical [CH3(X2A2'')]. The successful unraveling of this methyl-loss channel - through collaborative experimental and computational efforts - underscores the viability of the photolytically generated dicarbon beam as an unprecedented tool to access reaction dynamics underlying the formation of resonantly stabilized free radicals (RSFR) that are vital to molecular mass growth processes that ultimately lead to polycyclic aromatic hydrocarbons (PAHs).