Meningitis dipstick rapid test: evaluating diagnostic performance during an urban Neisseria meningitidis serogroup A outbreak, Burkina Faso, 2007.
Meningococcal meningitis outbreaks occur every year during the dry season in the "meningitis belt" of sub-Saharan Africa. Identification of the causative strain is crucial before launching mass vaccination campaigns, to assure use of the correct vaccine. Rapid agglutination (latex) tests are most commonly available in district-level laboratories at the beginning of the epidemic season; limitations include a short shelf-life and the need for refrigeration and good technical skills. Recently, a new dipstick rapid diagnostic test (RDT) was developed to identify and differentiate disease caused by meningococcal serogroups A, W135, C and Y. We evaluated the diagnostic performance of this dipstick RDT during an urban outbreak of meningitis caused by N. meningitidis serogroup A in Ouagadougou, Burkina Faso; first against an in-country reference standard of culture and/or multiplex PCR; and second against culture and/or a highly sensitive nested PCR technique performed in Oslo, Norway. We included 267 patients with suspected acute bacterial meningitis. Using the in-country reference standard, 50 samples (19%) were positive. Dipstick RDT sensitivity (N = 265) was 70% (95%CI 55-82) and specificity 97% (95%CI 93-99). Using culture and/or nested PCR, 126/259 (49%) samples were positive; dipstick RDT sensitivity (N = 257) was 32% (95%CI 24-41), and specificity was 99% (95%CI 95-100). We found dipstick RDT sensitivity lower than values reported from (i) assessments under ideal laboratory conditions (>90%), and (ii) a prior field evaluation in Niger [89% (95%CI 80-95)]. Specificity, however, was similar to (i), and higher than (ii) [62% (95%CI 48-75)]. At this stage in development, therefore, other tests (e.g., latex) might be preferred for use in peripheral health centres. We highlight the value of field evaluations for new diagnostic tests, and note relatively low sensitivity of a reference standard using multiplex vs. nested PCR. Although the former is the current standard for bacterial meningitis surveillance in the meningitis belt, nested PCR performed in a certified laboratory should be used as an absolute reference when evaluating new diagnostic tests.


Variations in the shape of the frontobasal brain region in obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) emerges during childhood through young adulthood coinciding with the late phases of postnatal brain development when fine remodeling of brain anatomy takes place. Previous research has suggested the existence of subtle anatomical alterations in OCD involving focal volume variations in different brain regions including the frontal lobes and basal ganglia. We investigated whether anatomical changes might also involve variations in the shape of the frontobasal region. A total of 101 OCD patients and 101 control subjects were examined using magnetic resonance imaging. A cross-sectional image highly representative of frontal-basal ganglia anatomy was selected in each individual and 25 reliable anatomical landmarks were identified to assess shape changes. A pixel-wise morphing approach was also used to dynamically illustrate the findings. We found significant group differences for overall landmark position and for most individual landmarks delimiting the defined frontobasal region. OCD patients showed a deformation pattern involving shortening of the anterior-posterior dimension of the frontal lobes and basal ganglia, and enlargement of cerebrospinal fluid spaces around the frontal opercula. In addition, we observed significant correlation of brain tissue shape variation with frontal sinus size. Identification of a global change in the shape of the frontobasal region may further contribute to characterizing the nature of brain alterations in OCD. The coincidence of brain shape variations with morphological changes in the frontal sinus indicates a potential association of OCD to late development disturbances, as the frontal sinus macroscopically emerges during the transition between childhood and adulthood.


Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within a secondary care setting.
The diagnosis of dementia relies on the presence of new-onset cognitive impairment affecting an individual's functioning and activities of daily living. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is a questionnaire instrument, completed by a suitable 'informant' who knows the patient well, designed to assess change in functional performance secondary to cognitive change; it is used as a tool to identifying those who may have dementia.In secondary care there are two specific instances where patients may be assessed for the presence of dementia. These are in the general acute hospital setting, where opportunistic screening may be undertaken, or in specialist memory services where individuals have been referred due to perceived cognitive problems. To ensure an instrument is suitable for diagnostic use in these settings, its test accuracy must be established. To determine the diagnostic accuracy of the informant-based questionnaire IQCODE, for detection of all-cause (undifferentiated) dementia in adults presenting to secondary-care services. We searched the following sources on the 28th of January 2013: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (Ovid SP), EMBASE (Ovid SP), PsycINFO (Ovid SP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection (includes Conference Proceedings Citation Index) (Thomson Reuters Web of Science), CINAHL (EBSCOhost) and LILACS (BIREME). We also searched sources specific to diagnostic test accuracy: MEDION (Universities of Maastricht and Leuven); DARE (Database of Abstracts of Reviews of Effects - via the Cochrane Library); HTA Database (Health Technology Assessment Database via the Cochrane Library) and ARIF (Birmingham University). We also checked reference lists of relevant studies and reviews, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on IQCODE for dementia diagnosis to try to find additional studies. We developed a sensitive search strategy; search terms were designed to cover key concepts using several different approaches run in parallel and included terms relating to cognitive tests, cognitive screening and dementia. We used standardised database subject headings such as MeSH terms (in MEDLINE) and other standardised headings (controlled vocabulary) in other databases, as appropriate. We selected those studies performed in secondary-care settings, which included (not necessarily exclusively) IQCODE to assess for the presence of dementia and where dementia diagnosis was confirmed with clinical assessment. For the 'secondary care' setting we included all studies which assessed patients in hospital (e.g. acute unscheduled admissions, referrals to specialist geriatric assessment services etc.) and those referred for specialist 'memory' assessment, typically in psychogeriatric services. We screened all titles generated by electronic database searches, and reviewed abstracts of all potentially relevant studies. Two independent assessors checked full papers for eligibility and extracted data. We determined quality assessment (risk of bias and applicability) using the QUADAS-2 tool, and reporting quality using the STARD tool. From 72 papers describing IQCODE test accuracy, we included 13 papers, representing data from 2745 individuals (n = 1413 (51%) with dementia). Pooled analysis of all studies using data presented closest to a cut-off of 3.3 indicated that sensitivity was 0.91 (95% CI 0.86 to 0.94); specificity 0.66 (95% CI 0.56 to 0.75); the positive likelihood ratio was 2.7 (95% CI 2.0 to 3.6) and the negative likelihood ratio was 0.14 (95% CI 0.09 to 0.22).There was a statistically significant difference in test accuracy between the general hospital setting and the specialist memory setting (P = 0.019), suggesting that IQCODE performs better in a 'general' setting.We found no significant differences in the test accuracy of the short (16-item) versus the 26-item IQCODE, or in the language of administration.There was significant heterogeneity in the included studies, including a highly varied prevalence of dementia (10.5% to 87.4%). Across the included papers there was substantial potential for bias, particularly around sampling of included participants and selection criteria, which may limit generalisability. There was also evidence of suboptimal reporting, particularly around disease severity and handling indeterminate results, which are important if considering use in clinical practice. The IQCODE can be used to identify older adults in the general hospital setting who are at risk of dementia and require specialist assessment; it is useful specifically for ruling out those without evidence of cognitive decline. The language of administration did not affect test accuracy, which supports the cross-cultural use of the tool. These findings are qualified by the significant heterogeneity, the potential for bias and suboptimal reporting found in the included studies.


Black carbon dominates the aerosol absorption over the Indo-Gangetic Plain and the Himalayan foothills.
This study, based on new and high quality in situ observations, quantifies for the first time, the individual contributions of light-absorbing aerosols (black carbon (BC), brown carbon (BrC) and dust) to aerosol absorption over the Indo-Gangetic Plain (IGP) and the Himalayan foothill region, a relatively poorly studied region with several sensitive ecosystems of global importance, as well as highly vulnerable populations. The annual and seasonal average single scattering albedo (SSA) over Kathmandu is the lowest of all the locations. The SSA over Kathmandu is < 0.89 during all seasons, which confirms the dominance of light-absorbing carbonaceous aerosols from local and regional sources over Kathmandu. It is observed here that the SSA decreases with increasing elevation, confirming the dominance of light absorbing carbonaceous aerosols at higher elevations. In contrast, the SSA over the IGP does not exhibit a pronounced spatial variation. BC dominates (≥75%) the aerosol absorption over the IGP and the Himalayan foothills throughout the year. Higher BC concentration at elevated locations in the Himalayas leads to lower SSA at elevated locations in the Himalayas. The contribution of dust to aerosol absorption is higher throughout the year over the IGP than over the Himalayan foothills. The aerosol absorption over South Asia is very high, exceeding available observations over East Asia, and also exceeds previous model estimates. This quantification will be valuable as observational constraints to help improve regional simulations of climate change, impacts on the glaciers and the hydrological cycle, and will help to direct the focus towards BC as the main contributor to aerosol-induced warming in the region.


Relationship between endogenous testosterone and cardiovascular risk in early postmenopausal women.
Cardiovascular disease (CVD) is the leading cause of death among postmenopausal women. Changes in endothelial function play an important role in the pathophysiology of atherosclerosis, and evidence suggests that interventions to improve endothelial function could modify the rates of progression and the risk of cardiovascular events. In addition, a positive association between markers of endothelial dysfunction and androgenicity has been described in women with polycystic ovary syndrome, suggesting a correlation with the early-onset endothelial dysfunction found in these patients. We performed a cross-sectional study to verify whether endogenous testosterone levels are correlated with markers of inflammation and endothelial function and with anthropometric and metabolic profile in 53 postmenopausal women. Serum testosterone, sex hormone-binding globulin, C-reactive protein (CRP), fibrinogen, and plasma endothelin-1 (ET-1) were determined. Patients were stratified into 2 groups (higher or lower than the mean testosterone levels of the studied sample). Mean age was 55 years (+/-5), and median time since menopause was 5.5 years (interquartile range, 3-8 years). Body mass index and waist circumference were significantly higher in the group with testosterone levels >or=0.49 ng/mL. Median CRP levels were greater in the group with higher testosterone levels (1.17 [0.17-2.36] vs 0.17 [0.17-0.61] mg/L, P = .039). Median ET-1 levels were also higher in women with greater testosterone levels (0.84 [0.81-0.97] vs 0.81 [0.74-0.84] pg/mL, P = .023). An association of testosterone with CRP (r = 0.416, P = .004) and ET-1 (r = 0.323, P = .031) was observed. This association was dependent on homeostasis model assessment index for ET-1 but not CRP. Testosterone was also associated with waist circumference and blood pressure (P = .001). These data suggest that endogenous testosterone levels in recently postmenopausal women may be part of a proatherogenic profile. Longitudinal studies are needed to assess if androgenicity represents a risk factor for cardiovascular disease and the clinical relevance of its association with ET-1 and CRP in this population.


Goats decrease hindlimb stiffness when walking over compliant surfaces.
Leg stiffness, commonly estimated as the 'compression' of a defined leg element in response to a load, has long been used to characterize terrestrial locomotion. This study investigated how goats adjust the stiffness of their hindlimbs to accommodate surfaces of different stiffness. Goats provide a compelling animal model for studying leg stiffness modulation, because they skillfully ambulate over a range of substrates that vary in compliance. To investigate the adjustments that goats make when walking over such substrates, ground reaction forces and three-dimensional trajectories of hindlimb markers were recorded as goats walked on rigid, rubber and foam surfaces. Net joint moments, power and work at the hip, knee, ankle and metatarsophalangeal joints were estimated throughout stance via inverse dynamics. Hindlimb stiffness was estimated from plots of total leg force versus total leg length, and individual joint stiffness was estimated from plots of joint moment versus joint angle. Our results support the hypothesis that goats modulate hindlimb stiffness in response to surface stiffness; specifically, hindlimb stiffness decreased on the more compliant surfaces (P<0.002). Estimates of joint stiffness identified hip and ankle muscles as the primary drivers of these adjustments. When humans run on compliant surfaces, they generally increase leg stiffness to preserve their center-of-mass mechanics. We did not estimate center-of-mass mechanics in this study; nevertheless, our estimates of hindlimb stiffness suggest that goats exhibit a different behavior. This study offers new insight into mechanisms that allow quadrupeds to modulate their gait mechanics when walking on surfaces of variable compliance.


Animal husbandry practices in rural Bangladesh: potential risk factors for antimicrobial drug resistance and emerging diseases.
Antimicrobial drug administration to household livestock may put humans and animals at risk for acquisition of antimicrobial drug-resistant pathogens. To describe animal husbandry practices, including animal healthcare-seeking and antimicrobial drug use in rural Bangladesh, we conducted semi-structured in-depth interviews with key informants, including female household members (n = 79), village doctors (n = 10), and pharmaceutical representatives, veterinarians, and government officials (n = 27), and performed observations at animal health clinics (n = 3). Prevalent animal husbandry practices that may put persons at risk for acquisition of pathogens included shared housing and water for animals and humans, antimicrobial drug use for humans and animals, and crowding. Household members reported seeking human and animal healthcare from unlicensed village doctors rather than formal-sector healthcare providers and cited cost and convenience as reasons. Five times more per household was spent on animal than on human healthcare. Strengthening animal and human disease surveillance systems should be continued. Interventions are recommended to provide vulnerable populations with a means of protecting their livelihood and health.


Results from South Africa's 2014 Report Card on Physical Activity for Children and Youth.
There is current concern for the health and well-being of children and youth in South Africa, including habits of physical activity (PA) and sedentary behavior. The 2014 Healthy Active Kids South Africa Report Card evaluates the current activity status of children and youth. The Research Working Group was comprised of 23 experts in physical education, nutrition, sport science, public health and journalism. The search was based on a systematic review of peer-reviewed literature (previous 5 years), dissertations, and nonpeer-reviewed reports ('gray' literature) dealing with the PA and nutritional status of South African children and youth 6-18 years of age. Key indicators were identified and data extracted. Grades for each indicator were discussed and assigned. Overall PA levels received a D grade, as roughly 50% or more of children and youth were not meeting recommended levels. Organized sports participation fared better with a C, and government policies were promising, receiving a B. Screen time and sedentary behavior were a major concern and received a grade of F. Under- and over-weight were highlighted, but overweight is on the rise and this indicator was assigned a D grade. Most of the other indicators in South Africa remained the same or became worse so that grades declined from C- to D. In particular, sedentary behavior, soft-drink and fast food consumption, and an ineffectual regulatory environment to control advertising to children were a concern. There is need to engage parents and communities for advocacy and social mobilization.


Microtiter plate cultivation of oleaginous fungi and monitoring of lipogenesis by high-throughput FTIR spectroscopy.
Oleaginous fungi can accumulate lipids by utilizing a wide range of waste substrates. They are an important source for the industrial production of omega-6 polyunsaturated fatty acids (gamma-linolenic and arachidonic acid) and have been suggested as an alternative route for biodiesel production. Initial research steps for various applications include the screening of fungi in order to find efficient fungal producers with desired fatty acid composition. Traditional cultivation methods (shake flask) and lipid analysis (extraction-gas chromatography) are not applicable for large-scale screening due to their low throughput and time-consuming analysis. Here we present a microcultivation system combined with high-throughput Fourier transform infrared (FTIR) spectroscopy for efficient screening of oleaginous fungi. The microcultivation system enables highly reproducible fungal fermentations throughout 12 days of cultivation. Reproducibility was validated by FTIR and HPLC data. Analysis of FTIR spectral ester carbonyl peaks of fungal biomass offered a reliable high-throughput at-line method to monitor lipid accumulation. Partial least square regression between gas chromatography fatty acid data and corresponding FTIR spectral data was used to set up calibration models for the prediction of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, unsaturation index, total lipid content and main individual fatty acids. High coefficients of determination (R2 = 0.86-0.96) and satisfactory residual predictive deviation of cross-validation (RPDCV = 2.6-5.1) values demonstrated the goodness of these models. We have demonstrated in this study, that the presented microcultivation system combined with rapid, high-throughput FTIR spectroscopy is a suitable screening platform for oleaginous fungi. Sample preparation for FTIR measurements can be automated to further increase throughput of the system.


Advanced Monitoring Systems Based on Battery-Less Asset Tracking Modules Energized through RF Wireless Power Transfer.
Asset tracking involving accurate location and transportation data is highly suited to wireless sensor networks (WSNs) featuring battery-less nodes that can be deployed in virtually any environment and require little or no maintenance. In response to the growing demand for advanced battery-less sensor tag solutions, this article presents a system for identifying and monitoring the speeds of assets in a WSN with battery-less tags that receive all their operating energy through radio frequency (RF) wireless power transfer (WPT) architecture, and a unique measurement approach to generate time-domain speed readouts. The assessment includes performance characteristics and key features of a system on chip (SoC) purposely designed to power a node through RF WPT. The result is an innovative solution for RF to DC conversion able to address the principal difficulties associated with maximum power conversion efficiency (PCE) with sensitivity and vice versa, a strategy, and a design optimization model to indicate the number of readers required for reliable asset identification and speed measurement. Model validation is performed through specific tests. Experimental results demonstrating the viability of the proposed advanced monitoring system are provided.


DACH1 negatively regulates the human RANK ligand gene expression in stromal/preosteoblast cells.
Receptor activator of NF-kappaB ligand (RANKL) is a critical osteoclastogenic factor that is expressed on bone marrow stromal/preosteoblast cells. Most bone resorption stimuli induce osteoclast formation by modulating RANKL expression in these cells. However, little is known about the mechanisms regulating RANKL gene expression. We recently reported that heat shock factor-2 (HSF-2) is a downstream target for FGF-2 signaling to enhance RANKL gene transcription in marrow stromal/preosteoblast cells. In this study, we show that DACH1 (human homologue of Drosophila dachshund gene) negatively regulates RANKL gene expression and suppresses FGF-2-enhanced RANKL gene expression in these cells. DACH1 contains a conserved dachshund domain (DS) in the N-terminal region, which interacts with the nuclear co-repressor (NCoR) to repress gene expression. Co-expression of DACH1 with hRANKL promoter-luciferase reporter plasmid in normal human bone marrow-derived stromal cells significantly decreased (3.3-fold) FGF-2-stimulated hRANKL gene promoter activity. Deletion of DS domain abolished DACH1 inhibition of FGF-2-enhanced RANKL gene promoter activity. Western blot analysis confirmed that DACH1 suppressed FGF-2-stimulated RANKL expression in marrow stromal/preosteoblast cells. We show HSF-2 co-immune precipitated with DACH1 and that FGF-2 stimulation significantly increased (2.7-fold) HSF-2 binding to DACH1. Confocal microscopy analysis further demonstrated that FGF-2 promotes HSF-2 nuclear transport and co-localization with DACH1 in marrow stromal cells. Co-expression of NCoR with DACH1 significantly decreased (5.3-fold) and siRNA suppression of NCoR in DACH1 co-transfected cells increased (3.6-fold) RANKL promoter activity. Furthermore, DACH1 co-expression with NCoR significantly decreased (7.5-fold) RANKL mRNA expression in marrow stromal cells. Collectively, these studies indicate that NCoR participates in DACH1 repression of RANKL gene expression in marrow stromal/preosteoblast cells. Thus, DACH1 plays an important role in negative regulation of RANKL gene expression in marrow stromal/preosteoblast cells in the bone microenvironment.


Regulation of the Bacillus subtilis ytmI operon, involved in sulfur metabolism.
The YtlI regulator of Bacillus subtilis activates the transcription of the ytmI operon encoding an l-cystine ABC transporter, a riboflavin kinase, and proteins of unknown function. The expression of the ytlI gene and the ytmI operon was high with methionine and reduced with sulfate. Using deletions and site-directed mutagenesis, a cis-acting DNA sequence important for YtlI-dependent regulation was identified upstream from the -35 box of ytmI. Gel mobility shift assays confirmed that YtlI specifically interacted with this sequence. The replacement of the sulfur-regulated ytlI promoter by the xylA promoter led to constitutive expression of a ytmI'-lacZ fusion in a ytlI mutant, suggesting that the repression of ytmI expression by sulfate was mainly at the level of YtlI synthesis. We further showed that the YrzC regulator negatively controlled ytlI expression while this repressor also acted on ytmI expression via YtlI. The cascade of regulation observed in B. subtilis is conserved in Listeria spp. Both a YtlI-like regulator and a ytmI-type operon are present in Listeria spp. Indeed, the Lmo2352 protein from Listeria monocytogenes was able to replace YtlI for the activation of ytmI expression and a lmo2352'-lacZ fusion was repressed in the presence of sulfate via YrzC in B. subtilis. A common motif, AT(A/T)ATTCCTAT, was found in the promoter region of the ytlI and lmo2352 genes. Deletion of part of this motif or the introduction of point mutations in this sequence confirmed its involvement in ytlI regulation.


Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals.
Cholesteryl ester deficiency which results in adrenal lipid store depletion has been proposed as a potential mechanism of sepsis associated adrenal insufficiency. We investigated histological abnormalities associated with sepsis in human and mice adrenals. From January 2006 to 2008, seven patients who died of septic shock and seven patients with rapidly fatal nonseptic illness were included. Adrenals were sampled within 12 h from death. Adrenals were also taken from 13 lipopolysaccharide (LPS)-challenged mice, 5 cecal ligation and puncture (CLP) mice and 5 controls. We semi-quantitatively analysed intensity of inflammation, necrosis, haemorrhage and lipid depletion. In patients, lipid depletion scores were significantly higher in septic shock than in controls (p = 0.011). In animals, lipid depletion was higher following LPS or CLP than in controls (p = 0.003). In adrenal cortex, in patients and not in animals, global scores for inflammation (p = 0.002), necrosis (p = 0.009) and haemorrhage (p = 0.009) were significantly higher in septic shock than in controls. Similarly, in zona fasciculata, in patients and not in animals, scores for inflammation (p = 0.007), necrosis (p = 0.023) and haemorrhage (p = 0.023) were significantly higher in septic shock than in controls. This study shows that diffuse lipid depletion in zona fasciculata is a hallmark of human septic shock, experimental endotoxaemia and sepsis. In patients, sepsis was associated with inflammation, necrosis and haemorrhage predominantly in zona fasciculata.


Intraaneurysmal flow visualization by using phase-contrast magnetic resonance imaging: feasibility study based on a geometrically realistic in vitro aneurysm model.
The aim of this study was to evaluate the feasibility of complex intraaneurysmal flow visualization with the currently available phase-contrast magnetic resonance (MR) imaging modality. A geometrically realistic in vitro aneurysm model, in which detailed flow velocity analysis had already been conducted using laser Doppler velocimetry was used for this in vitro hemodynamic simulation, so that the results of phase-contrast velocity measurements could be compared with the previous reliable results. On a 1.5-tesla unit, three orthogonal components of velocity were obtained using a standard two-dimensional fast low-angle shot flow quantification sequence. Three-dimensional (3D) intraaneurysmal flow structures recorded during one cardiac cycle were depicted in one midsagittal and three axial cross-sectional planes with the aid of gray scale phase-contrast velocity maps. Isovelocity contour maps and secondary flow vectors were also created based on the phase-contrast velocity maps by using MATLAB software. The isovelocity contours in those three axial sections could demonstrate the shapes of inward and outward flow areas and their alternation over one cardiac cycle. The secondary flow vectors demonstrated twin vortices within the outward flow area adjacent to the boundary layer of inward and outward flow in all axial planes. The phase-contrast MR imaging method was able to depict the complex 3D intraaneurysmal flow structures in the in vitro aneurysm model. Detailed 3D intraaneurysmal flow information will be obtainable in vivo after improvements are made in spatial resolution, which is expected in the near future. The capability to visualize intraaneurysmal flow structures directly with the use of noninvasive MR imaging technology will have a positive impact on future clinical practice.


Impact of palm date consumption on microbiota growth and large intestinal health: a randomised, controlled, cross-over, human intervention study.
The reported inverse association between the intake of plant-based foods and a reduction in the prevalence of colorectal cancer may be partly mediated by interactions between insoluble fibre and (poly)phenols and the intestinal microbiota. In the present study, we assessed the impact of palm date consumption, rich in both polyphenols and fibre, on the growth of colonic microbiota and markers of colon cancer risk in a randomised, controlled, cross-over human intervention study. A total of twenty-two healthy human volunteers were randomly assigned to either a control group (maltodextrin-dextrose, 37·1 g) or an intervention group (seven dates, approximately 50 g). Each arm was of 21 d duration and was separated by a 14-d washout period in a cross-over manner. Changes in the growth of microbiota were assessed by fluorescence in situ hybridisation analysis, whereas SCFA levels were assessed using HPLC. Further, ammonia concentrations, faecal water genotoxicity and anti-proliferation ability were also assessed using different assays, which included cell work and the Comet assay. Accordingly, dietary intakes, anthropometric measurements and bowel movement assessment were also carried out. Although the consumption of dates did not induce significant changes in the growth of select bacterial groups or SCFA, there were significant increases in bowel movements and stool frequency (P<0·01; n 21) and significant reductions in stool ammonia concentration (P<0·05; n 21) after consumption of dates, relative to baseline. Furthermore, date fruit intake significantly reduced genotoxicity in human faecal water relative to control (P<0·01; n 21). Our data indicate that consumption of date fruit may reduce colon cancer risk without inducing changes in the microbiota.


Personality as a prognostic factor for specialty choice: a prospective study of 4 medical school classes.
To augment the availability of medical care for a population that is older and more ethnically diverse, the number of US medical schools is increasing and existing medical schools are enlarging their class sizes. Predictors of specialty choice, especially primary care careers, are helpful to medical school officials and faculty involved in medical school recruitment and counseling and to students planning their career paths. The objective was to examine the association between personality characteristics and specialty choice. The Neuroticism-Extraversion-Openness Personality Inventory Revised (NEO PI-R) was administered to 4 Tulane University School of Medicine (New Orleans, Louisiana) classes (2003-2006). The NEO PI-R is a measure of 5 personality characteristics (neuroticism, extraversion, openness, agreeableness, and conscientiousness), with each domain having 6 underlying facets. The specialty choice of graduates was obtained from the National Residency Matching Program. Starting in 1999, 595 students matriculated and by June 2006, 542 (91%) had matched to residency programs in 22 specialties. There were differences among specialties for neuroticism (P = .006), openness (P < .001), and agreeableness (P = .003), but not for extraversion (P = .173) or conscientiousness (P = .103). Various pairwise differences between specialty categories were found. Eleven specialty categories were compared using the NEO PI-R. Numerous specialty variations were identified for neuroticism, openness, and agreeableness. The findings may be useful to medical school officials and faculty who recruit and counsel students and to students themselves as they reflect on their personality characteristics on their path to making career choices.


Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney.
Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-β (TGF-β) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease.


Phosphatidylcholine in the groove of endothelial cell protein C receptor (EPCR) regulates EPCR conformation and protein C recognition.
Endothelial cell protein C receptor (EPCR), the cellular receptor for protein C (PC), facilitates PC activation through the thrombin/thrombomodulin complex and regulates thrombin generation. Under pathophysiological conditions like sepsis, the interactions between EPCR and PC become impaired. Previous studies have demonstrated that the EPCR contains a phospholipid in the antigen-binding groove that is responsible for the structural stability of the EPCR and for PC recognition. However, an understanding at the atomic level during ligand recognition is not fully developed. Molecular dynamics simulations along with potential of mean force (PMF) calculations were carried out in order to provide molecular insight into the dynamics and free energies of EPCR-PC in the absence/presence of phospholipid, namely lysophosphatidylcholine (lysoPCh) and phosphatidylcholine (PCh) in the antigen-binding groove of the EPCR. Our data reveal that the presence of lipid maintains the optimal conformation of the EPCR for PC binding. PMF data further suggest that the PCh system is the most stable in comparison with the other systems (lysoPCh and no lipid). With regards to the two hydrophobic tails of PCh, one lipid tail regulates EPCR conformation while the other promotes ligand recognition by interacting with the keel residue (Phe-4) of PC. Due to the lack of one hydrophobic tail for the lysoPCh system, the EPCR conformation is retained but the affinity of the EPCR towards the ligand (PC) is reduced. Our studies for the first time explore the possible mode of ligand recognition by the EPCR via the involvement of phosphatidylcholine within its hydrophobic groove. The present work provides insight into PCh-dependent ligand recognition and hence regulation of the protein C/EPCR complex formation.


Leptospirosis in pigs, dogs, rodents, humans, and water in an area of the Colombian tropics.
Leptospirosis is a reemerging zoonosis of global distribution and is one of the causes of hemorrhagic fevers in the tropics. We sought to determine seroprevalence in humans and animals and isolate Leptospira interrogans sensu lato in domestic animals, rodents, and water sources. The study was conducted in a tropical area of the middle Sinú in Cordoba, Colombia. In a prospective descriptive study, we collected blood and urine from pigs and dogs, sera from rural human workers, sera and kidney macerates of rodents, and water samples from environmental sources. We used microagglutination to screen for antibodies to 13 serovars. Strains were cultured on the Ellinghausen-McCullough-Johnson-Harris medium and confirmed by PCR amplifying lipL32 gene. Seroprevalence was 55.9% in pigs, 35.2% in dogs, and 75.8% in humans; no antibody was detected, and no Leptospira were isolated from kidney macerates of rodents. Seven L. interrogans sensu lato strains were isolated: three from pigs, two from dogs, and two from water. High seroprevalence in pigs, dogs, and humans, concomitant to isolation of strains, demonstrates that in Cordoba, transmission exists among animals, the environment, and humans, which warrants the implementation of public health intervention measures to reduce the epidemiological impact of leptospirosis in the region.


Worldwide research productivity on tramadol: a bibliometric analysis.
Pain management and safe use of analgesics is an important medical issue. Tramadol is an old analgesic with controversial properties. Evaluation of worldwide scientific output on tramadol has not been explored. Therefore, the main objective of this study was to give a bibliometric overview of global research productivity on tramadol. SciVerse Scopus was used to retrieve and quantitatively and qualitatively analyze worldwide publications on tramadol. A total of 2059 original and review research articles on tramadol were retrieved from Scopus. Forty-six documents (2.23 %) were published in Anesthesia and Analgesia Journal whereas 30 (1.46 %) were published in Arzneimittel Forschung Drug Research Journal. Retrieved tramadol documents were published from 71 countries and appeared in 160 peer reviewed journals. Although the United States of America (259; 12.86 %) had the largest contribution to tramadol publications; the contribution by other countries like Turkey (232; 11.27) India (189; 8.09 %) and Germany (176; 8.56 % was not far away from that of USA. The most productive institution was Grunenthal, Germany (47; 2.28 %) followed by Tehran University of Medical Sciences, Iran (29; 1.41 %), and, Ortho-McNeil Pharmaceutical Incorporated, USA (25; 1.21 %). Of the 2059 documents, there were 370 documents about dependence. The leading institution in documents pertaining to tramadol dependence was Grunenthal GmbH (18; 4.86 %) followed by Ortho-McNeil Pharmaceutical Incorporated (17; 4.59 %). The current study showed that there is an obvious interest in tramadol research. More efforts are needed to clarify the abuse potential and safety profile of tramadol to help in determining the legal status of tramadol. Collaboration among pharmaceutical industry, clinical researchers and academic institutions can improve research quantity and quality on tramadol.


Binocular photophobia after surgical treatment in intermittent exotropia.
This study examined the rate of binocular photophobia in intermittent exotropia patients before surgical correction, and the factors affecting this rate. The study also investigated the factors affecting postsurgical disappearance of binocular photophobia. The study involved 162 basic type intermittent exotropia patients who underwent surgical correction between March 2001 and January 2006. The study did not include patients with entropion, congenital cataract, or retinal abnormalities. Parents of the patients were questioned to determine which patients had monocular eye closure in bright light and which had disappeared after bilateral lateral rectus recession. Data was analyzed to determine the factors affecting monocular eye closure before surgery and disappearance after surgery. Of 162 patients, 96 patients had binocular photophobia (60.2%). Photophobia was found to be associated with an angle of exodeviation at distance >25 Prism Diopter (Delta) (p = 0.02), and stereoacuity worse than 60 s (p = 0.02). We defined satisfactory surgical outcome as a deviation of <10 Delta. Of the 81 patients with satisfactory outcomes, 46 showed disappearance of binocular photophobia (53.5%). No factor was found to be associated with loss of binocular photophobia. The angle of strabismus and stereoacuity were found to affect the occurrence of binocular photophobia. Successful surgery treated binocular photophobia in 53.5% of patients. Regardless of the surgical result, clinicians should educate patients in terms of the possibility of persistence of postsurgical photophobia.


Chloride-Mediated Enhancement in Heat-Induced Activation of Peroxymonosulfate: New Reaction Pathways for Oxidizing Radical Production.
This study is the first to demonstrate the capability of Cl- to markedly accelerate organic oxidation using thermally activated peroxymonosulfate (PMS) under acidic conditions. The treatment efficiency gain allowed heat-activated PMS to surpass heat-activated peroxydisulfate (PDS). During thermal PMS activation at excess Cl-, accelerated oxidation of 4-chlorophenol (susceptible to oxidation by hypochlorous acid (HOCl)) was observed along with significant degradation of benzoic acid and ClO3- occurrence, which involved oxidants with low substrate specificity. This indicated that heat facilitated HOCl formation via nucleophilic Cl- addition to PMS and enabled free chlorine conversion into less selective oxidizing radicals. HOCl acted as a key intermediate in the major oxidant transition based on temperature-dependent variation in HOCl concentration profiles, kinetically retarded organic oxidation upon NH4+ addition, and enabled rapid organic oxidation in heated PMS/HOCl mixtures. Chlorine atom that formed via the one-electron oxidation of Cl- by the sulfate radical served as the primary oxidant and was involved in hydroxyl radical production. This was corroborated by the quenching effects of alcohols and bicarbonates, reactivity toward multiple organics, and electron paramagnetic resonance spectral features. PMS outperformed PDS in degrading benzoic acid during thermal activation operated in reverse osmosis concentrate, which was in conflict with the well-established superiority of heat-activated PDS.


[Membranoproliferative glomerulonephritis with semilunar forms and massive deposits of IgA associated with HBsAg].
The association of HBV infection and glomerular damage was first reported by Combes et al in 1971, in a patient with nephrotic syndrome due to membranous glomerulopathy and chronic hepatitis B. Since, then, other glomerular diseases have been reported such as a) minimal changes nephropathy, b) IgA nephropathy, c) membranous-proliferative glomerulonephritis (MPGN), d) membranous, e) mesangial proliferative and f) lupus nephritis. All of them are associated with chronic hepatic disease and some of the following antigens: 1) HBsAg; 2) HBeAg; 3) HBcAg. These disorders are very frequent in Southeast Asia. Vertical transmission from mothers to fetuses may be important in maintaining the high carrier rate, and possibly plays a role in the development of glomerular damage. On the other hand, MPGN associated with HBsAg has rarely been reported and always with a favorable benign course. The present report describes interesting findings in a renal biopsy from a HBsAg and HBeAg carrier, who developed renal failure requiring hemodialysis. A 21 year old Korean man was admitted to the Hospital for nephrotic syndrome, microhematuria hypertension and renal failure. He had no previous history of blood transfusion, intravenous drug addiction, jaundice or liver disease. His father was HBsAg carrier with hepatic cirrhosis. An ultrasound examination showed normal renal size. Renal biopsy was performed and the patient received hemodialysis treatment. The specimen was processed for light microscopy, immunofluorescent studies and peroxidase-antiperoxidase technique. Frozen sections were studied by direct immunofluorescence for the identification of IgG, IgA, C1q, C3, fibrinogen and albumin. Paraffin sections stained by immunoperoxidase technique for HBsAg, using polyclonal monospecific rabbit anti-Human antisera (Dakopatts, Copenhagen).(ABSTRACT TRUNCATED AT 250 WORDS)


Host phenology and geography as drivers of differentiation in generalist fungal mycoparasites.
The question as to why parasites remain generalist or become specialist is a key unresolved question in evolutionary biology. Ampelomyces spp., intracellular mycoparasites of powdery mildew fungi, which are themselves plant pathogens, are a useful model for studies of this issue. Ampelomyces is used for the biological control of mildew. Differences in mycohost phenology promote temporal isolation between sympatric Ampelomyces mycoparasites. Apple powdery mildew (APM) causes spring epidemics, whereas other powdery mildew species on plants other than apple cause epidemics later in the season. This has resulted in genetic differentiation between APM and non-APM strains. It is unclear whether there is genetic differentiation between non-APM Ampelomyces lineages due to their specialization on different mycohosts. We used microsatellites to address this question and found no significant differentiation between non-APM Ampelomyces strains from different mycohosts or host plants, but strong differentiation between APM and non-APM strains. A geographical structure was revealed in both groups, with differences between European countries, demonstrating restricted dispersal at the continent scale and a high resolution for our markers. We found footprints of recombination in both groups, possibly more frequent in the APM cluster. Overall, Ampelomyces thus appears to be one of the rare genuine generalist pathogenic fungi able to parasitize multiple hosts in natural populations. It is therefore an excellent model for studying the evolution of pathogens towards a generalist rather than host-specific strategy, particularly in light of the tritrophic interaction between Ampelomyces mycoparasites, their powdery mildew fungal hosts and the mildew host plants.


Effect of Vascular Injury on Functional Outcome in Knees with Multi-Ligament Injury: A Matched-Cohort Analysis.
Multi-ligament knee injury (MLKI) associated with knee dislocation can result in vascular injury. The purpose of this study was to compare knee function after MLKI between patients with a vascular injury requiring popliteal artery bypass grafting and patients without vascular involvement. Additionally, factors associated with poor knee function in patients who had MLKI with vascular injury were evaluated. This retrospective study identified patients with an MLKI between 1992 and 2014. Each patient who had a concomitant vascular injury requiring bypass grafting (vascular cohort, n = 16; mean age, 30.3 years) was matched to 2 patients without a vascular injury (control cohort, n = 32; mean age, 31.4 years) on the basis of age, knee dislocation (KD) grade, and peroneal nerve status. Fifteen patients in the vascular cohort and 26 patients in the control cohort had an isolated knee injury. Functional outcomes were assessed with physical examination of range of motion and ligamentous stability as well as patient-reported outcome scores. The vascular cohort had a mean Lysholm score of 62.5 points (range, 16 to 100 points) and a mean International Knee Documentation Committee (IKDC) score of 59.7 points (range, 14.9 to 100 points) at a mean (and standard deviation) of 8.3 ± 5.0 years after surgery. The control cohort had a mean Lysholm score of 86.4 points (range, 51.0 to 100.0 points) and a mean IKDC score of 83.8 points (range, 35.6 to 100.0 points) at a mean of 6.0 ± 4.0 years. The vascular cohort had significantly lower Lysholm (p = 0.001) and IKDC (p = 0.002) scores than the control cohort. A body mass index (BMI) of >30 kg/m was predictive of lower IKDC (p = 0.0009) and Lysholm (p = 0.0008) scores. Patients who sustain an MLKI with an associated popliteal artery injury requiring bypass grafting have significantly lower knee function scores than patients without vascular involvement. This information can be used to help counsel patients with combined multiple ligament and popliteal artery injuries. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Nanoscale structure and dynamics of ABOBEC3G complexes with single-stranded DNA.
The DNA cytosine deaminase APOBEC3G (A3G) is capable of blocking retrovirus replication by editing viral cDNA and impairing reverse transcription. However, the biophysical details of this host-pathogen interaction are unclear. We applied atomic force microscopy (AFM) and hybrid DNA substrates to investigate properties of A3G bound to single-stranded DNA (ssDNA). Hybrid DNA substrates included ssDNA with 5' or 3' ends attached to DNA duplexes (tail-DNA) and gap-DNA substrates, in which ssDNA is flanked by two double-stranded fragments. We found that A3G binds with similar efficiency to the 5' and 3' substrates, suggesting that ssDNA polarity is not an important factor. Additionally, we observed that A3G binds the single-stranded region of the gap-DNA substrates with the same efficiency as tail-DNA. These results demonstrate that single-stranded DNA ends are not needed for A3G binding. The protein stoichiometry does not depend on the ssDNA substrate type, but the ssDNA length modulates the stoichiometry of A3G in the complex. We applied single-molecule high-speed AFM to directly visualize the dynamics of A3G in the complexes. We were able to visualize A3G sliding and protein association-dissociation events. During sliding, A3G translocated over a 69-nucleotide ssDNA segment in <1 s. Association-dissociation events were more complex, as dimeric A3G could dissociate from the template as a whole or undergo a two-step process with monomers capable of sequential dissociation. We conclude that A3G monomers, dimers, and higher-order oligomers can bind ssDNA substrates in a manner independent of strand polarity and availability of free ssDNA ends.


ALS and mercury intoxication: a relationship?
We report the case of an 81-year-old woman in whom clinical signs and features of electromyographic activity patterns were consistent with amyotrophic lateral sclerosis (ALS). Increased blood level and massive urinary excretion of mercury proved mercury intoxication. Despite a chelation treatment with Meso 2-3 dimercaptosuccininc acid (DMSA), she died after 17 months. The pathophysiology of sporadic ALS remains unclear. However, the role of environmental factors has been suggested. Among some environmental factors, exposure to heavy metals has been considered and ALS cases consecutive to occupational intoxication and accidental injection of mercury have been reported. Although no autopsy was performed, we discuss the role of mercury intoxication in the occurrence of ALS in our case, considering the results of experimental studies on the toxicity of mercury for motor neuron.


Pushing typists back on the learning curve: revealing chunking in skilled typewriting.
Theories of skilled performance propose that highly trained skills involve hierarchically structured control processes. The present study examined and demonstrated hierarchical control at several levels of processing in skilled typewriting. In the first two experiments, we scrambled the order of letters in words to prevent skilled typists from chunking letters, and compared typing words and scrambled words. Experiment 1 manipulated stimulus quality to reveal chunking in perception, and Experiment 2 manipulated concurrent memory load to reveal chunking in short-term memory (STM). Both experiments manipulated the number of letters in words and nonwords to reveal chunking in motor planning. In the next two experiments, we degraded typing skill by altering the usual haptic feedback by using a laser-projection keyboard, so that typists had to monitor keystrokes. Neither the number of motor chunks (Experiment 3) nor the number of STM items (Experiment 4) was influenced by the manipulation. The results indicate that the utilization of hierarchical control depends on whether the input allows chunking but not on whether the output is generated automatically. We consider the role of automaticity in hierarchical control of skilled performance.


Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth.
The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.


Ellen R. Grass Lecture: Motor evoked potential monitoring.
Because somatosensory evoked potentials (SSEPs) recorded from the brain are carried solely within the dorsal columns of the spinal cord, SSEP monitoring may fail to detect damage to the spinal cord motor pathways, and techniques for directly monitoring the motor pathways have been developed. Transcranial magnetic brain stimulation is useful for extraoperative evaluation of the motor system, but anesthetic effects on cortical synaptic activity limit its usefulness for intraoperative monitoring. Another proposed monitoring technique, rostral spinal cord stimulation with recording from peripheral nerves, predominantly reflects retrograde conduction within the dorsal columns; like SSEPs, this technique may fail to detect motor pathway damage. The true motor evoked potential (MEP) monitoring technique preferred by most institutions involves transcranial electrical brain stimulation. This stimulates the corticospinal tract axons directly, producing a D-wave in them. There may be additional corticospinal tract volleys, reflecting indirect activation of the pyramidal cells via synapses from cortical interneurons; these I-waves are largely suppressed by anesthesia. Temporal summation at the alpha motor neuron synapse is necessary to elicit myogenic MEPs (M-waves) under anesthesia; this is accomplished with brief trains of stimuli that produce multiple pyramidal tract volleys. High stimulus intensities are required to stimulate the brain through an intact skull; with proper precautions, this is acceptably safe. Myogenic MEPs are quite sensitive to anesthesia and show considerable run-to-run variability. Therefore, criteria for evaluating MEPs differ from those for SSEPs, and the anesthetic regimen and degree of neuromuscular blockade must be carefully controlled. SSEPs should be monitored concurrently with MEPs, because the dorsal columns may be affected without compromise of the motor tracts, and also because this provides redundancy, with two independent assessments of spinal cord function.


Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens.
Human noroviruses are the leading causative agents of epidemic and sporadic viral gastroenteritis and childhood diarrhoea worldwide. Human histo-blood group antigens (HBGA) serve as receptors for norovirus capsid protein attachment and play a critical role in infection. This makes HBGA-norovirus binding a promising target for drug development. Recently solved crystal structures of norovirus bound to HBGA have provided a structural basis for identification of potential anti-norovirus drugs and subsequently performed in silico and in vitro drug screens have identified compounds that block norovirus binding and may thereby serve as structural templates for design of therapeutic norovirus inhibitors. This review explores norovirus therapeutic options based on the strategy of blocking norovirus-HBGA binding.


Cell index--a new parameter for the early diagnosis of ventriculostomy (external ventricular drainage)-related ventriculitis in patients with intraventricular hemorrhage?
Temporary intraventricular catheters for managing acute obstructive hydrocephalus caused by intraventricular haemorrhage carry a high risk of developing ventriculostomy-related ventriculitis (VRV). The aim of this prospective study was to validate a new parameter for the early detection of an intraventricular infection. Patients with external ventricular drainage due to intraventricular haemorrhage were enrolled in this prospective study. Leucocytes and erythrocytes in cerebrospinal fluid (CSF) and peripheral blood as well as bacteriological and chemical analysis of both were examined daily. The ratio of leucocytes to erythrocytes in CSF and leucocytes to erythrocytes in peripheral blood was calculated (so called cell index (CI)) and these values were compared with the "conventionally diagnosed" drain-associated ventriculitis. Furthermore, the CI values of the non-ventriculitis and ventriculitis group were compared using the t-test with adjustment for unequal variances (Welch test). Thirteen patients with an external ventricular drainage (EVD) expected to be in place for more than seven days were enrolled. Seven patients developed a bacteriologically proven VRV (time 0) within 12 days (mean 8.57). Diagnosis of VRV by CI was possible up to 3 days (mean 2.28) prior to conventional diagnosis. P values (Welch test) showed a significant difference on days -3 (P = 0.03), -2 (P = 0.03) and -1 (P = 0.012) - i.e. 3, 2 or 1 day, respectively, prior to the time point when the CSF culture grew staphylococci -, when compared with the mean cell indices of the controls, and a highly significant difference on time 0 (P < 0.001). The calculated CI allows the diagnosis of nosocomial VRV in patients with intraventricular haemorrhage at a very early point of time.


Study of the Ability of Bifidobacteria of Human Origin to Prevent and Treat Rotavirus Infection Using Colonic Cell and Mouse Models.
Rotavirus is the leading cause of severe acute gastroenteritis among children worldwide. Despite effective vaccines, inexpensive alternatives such as probiotics are needed. The aim of this study was to assess the ability of probiotic candidate Bifidobacterium thermophilum RBL67 to inhibit rotavirus infection. Bacterial adhesion to intestinal cells and interference with viral attachment were evaluated in vitro. B. thermophilum RBL67 displayed adhesion indexes of 625 ± 84 and 1958 ± 318 on Caco-2 and HT-29 cells respectively and was comparable or superior to four other bifidobacteria, including B. longum ATCC 15707 and B. pseudolongum ATCC 25526 strains. Incubation of B. thermophilum RBL67 for 30 min before (exclusion) and simultaneously (competition) with human rotavirus strain Wa decreased virus attachment by 2.0 ± 0.1 and 1.5 ± 0.1 log10 (by 99.0% and 96.8% respectively). Displacement of virus already present was negligible. In CD-1 suckling mice fed B. thermophilum RBL67 challenged with simian rotavirus SA-11, pre-infection feeding with RBL 67 was more effective than post-infection feeding, reducing the duration of diarrhea, limiting epithelial lesions, reducing viral replication in the intestine, accelerating recovery, and stimulating the humoral specific IgG and IgM response, without inducing any adverse effect. B. thermophilum RBL67 had little effect on intestinal IgA titer. These results suggest that humoral immunoglobulin might provide protection against the virus and that B. thermophilum RBL67 has potential as a probiotic able to inhibit rotavirus infection and ultimately reduce its spread.


Image-Based Biological Heart Age Estimation Reveals Differential Aging Patterns Across Cardiac Chambers.
Biological heart age estimation can provide insights into cardiac aging. However, existing studies do not consider differential aging across cardiac regions. To estimate biological age of the left ventricle (LV), right ventricle (RV), myocardium, left atrium, and right atrium using magnetic resonance imaging radiomics phenotypes and to investigate determinants of aging by cardiac region. Cross-sectional. A total of 18,117 healthy UK Biobank participants including 8338 men (mean age = 64.2 ± 7.5) and 9779 women (mean age = 63.0 ± 7.4). A 1.5 T/balanced steady-state free precession. An automated algorithm was used to segment the five cardiac regions, from which radiomic features were extracted. Bayesian ridge regression was used to estimate biological age of each cardiac region with radiomics features as predictors and chronological age as the output. The "age gap" was the difference between biological and chronological age. Linear regression was used to calculate associations of age gap from each cardiac region with socioeconomic, lifestyle, body composition, blood pressure and arterial stiffness, blood biomarkers, mental well-being, multiorgan health, and sex hormone exposures (n = 49). Multiple testing correction with false discovery method (threshold = 5%). The largest model error was with RV and the smallest with LV age (mean absolute error in men: 5.26 vs. 4.96 years). There were 172 statistically significant age gap associations. Greater visceral adiposity was the strongest correlate of larger age gaps, for example, myocardial age gap in women (Beta = 0.85, P = 1.69 × 10-26 ). Poor mental health associated with large age gaps, for example, "disinterested" episodes and myocardial age gap in men (Beta = 0.25, P = 0.001), as did a history of dental problems (eg LV in men Beta = 0.19, P = 0.02). Higher bone mineral density was the strongest associate of smaller age gaps, for example, myocardial age gap in men (Beta = -1.52, P = 7.44 × 10-6 ). This work demonstrates image-based heart age estimation as a novel method for understanding cardiac aging. 1. Stage 1.


KChIP4a regulates Kv4.2 channel trafficking through PKA phosphorylation.
Voltage-gated potassium (Kv) channels play important roles in regulating the excitability of myocytes and neurons. Kv4.2 is the primary alpha-subunit of the channel that produces the A-type K(+) current in CA1 pyramidal neurons of the hippocampus, which is critically involved in the regulation of dendritic excitability and plasticity. K(+) channel-interacting proteins, KChIPs (KChIP1-4), associate with the N-terminal of Kv4.2 and modulate the channel's biophysical properties, turnover rate and surface expression. In the present study, we investigated the role of Kv4.2 C-terminal PKA phosphorylation site S552 in the KChIP4a-mediated effects on Kv4.2 channel trafficking. We found that while interaction between Kv4.2 and KChIP4a does not require PKA phosphorylation of Kv4.2(S552), phosphorylation of this site is necessary for both enhanced stabilization and membrane expression of Kv4.2 channel complexes produced by KChIP4a. Enhanced surface expression and protein stability conferred by co-expression of Kv4.2 with other KChIP isoforms did not require PKA phosphorylation of Kv4.2 S552. Finally, we identify A-kinase anchoring proteins (AKAPs) as Kv4.2 binding partners, allowing for discrete local PKA signaling. These data demonstrate that PKA phosphorylation of Kv4.2 plays an important role in the trafficking of Kv4.2 through its specific interaction with KChIP4a.


Endoscopic Subureteral Injection for the Treatment of Vesicoureteral Reflux in Children: Polydimethylsiloxane (Macroplastique(R)) versus Dextranomer/Hyaluronic Acid Copolymer (Deflux(R)).
The aim of this study was to compare cure rates and complications of polydimethylsiloxane (Macroplastique(R)) and dextranomer/hyaluronic acid copolymer (Deflux(R)) in the treatment of vesicoureteral reflux (VUR). From April 2001 to March 2008, 29 boys and 42 girls (total of 115 ureters) with a mean age of 6 years who had undergone endoscopic subureteral transurethral injection for VUR were enrolled. A single subureteral injection of Macroplastique was performed in 31 ureters in 23 children (group I; grade II: 4; grade III: 12; grade IV: 9; grade V: 6), and a single subureteral injection of Deflux was performed in 84 ureters in 48 children (group II; grade II: 24; grade III: 14; grade IV: 25; grade V: 21). Renal ultrasound was done 1 day after injection, and voiding cystourethrography (VCUG) was done at 3 months. Successful reflux correction was defined as absent or grade I reflux on follow-up VCUG. No significant difference in success rates was observed between group I and group II [80.6% (25/31) vs. 78.6% (66/84), respectively, p>0.05]. The following postoperative complications developed: ureteral obstruction in 2 ureters of group I and 3 ureters of group II, asymptomatic urinary tract infection in 3 patients of group I and 2 patients of group II, and bladder calcification by erosion or mucosal necrosis in 2 patients of group I. Despite differences in material properties, both Macroplastique and Deflux were safe for the treatment of children with VUR. Because of the risk of bladder mucosal necrosis and substantial decreases in volume after implantation, long-term follow-up is required.


Personal genome testing: test characteristics to clarify the discourse on ethical, legal and societal issues.
As genetics technology proceeds, practices of genetic testing have become more heterogeneous: many different types of tests are finding their way to the public in different settings and for a variety of purposes. This diversification is relevant to the discourse on ethical, legal and societal issues (ELSI) surrounding genetic testing, which must evolve to encompass these differences. One important development is the rise of personal genome testing on the basis of genetic profiling: the testing of multiple genetic variants simultaneously for the prediction of common multifactorial diseases. Currently, an increasing number of companies are offering personal genome tests directly to consumers and are spurring ELSI-discussions, which stand in need of clarification. This paper presents a systematic approach to the ELSI-evaluation of personal genome testing for multifactorial diseases along the lines of its test characteristics. This paper addresses four test characteristics of personal genome testing: its being a non-targeted type of testing, its high analytical validity, low clinical validity and problematic clinical utility. These characteristics raise their own specific ELSI, for example: non-targeted genetic profiling poses serious problems for information provision and informed consent. Questions about the quantity and quality of the necessary information, as well as about moral responsibilities with regard to the provision of information are therefore becoming central themes within ELSI-discussions of personal genome testing. Further, the current low level of clinical validity of genetic profiles raises questions concerning societal risks and regulatory requirements, whereas simultaneously it causes traditional ELSI-issues of clinical genetics, such as psychological and health risks, discrimination, and stigmatization, to lose part of their relevance. Also, classic notions of clinical utility are challenged by the newer notion of 'personal utility.' Consideration of test characteristics is essential to any valuable discourse on the ELSI of personal genome testing for multifactorial diseases. Four key characteristics of the test - targeted/non-targeted testing, analytical validity, clinical validity and clinical utility - together determine the applicability and the relevance of ELSI to specific tests. The paper identifies and discusses four areas of interest for the ELSI-debate on personal genome testing: informational problems, risks, regulatory issues, and the notion of personal utility.


Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma.
Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine-glycine-aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in αvβ3 integrin-expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting.


Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis.
It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti-TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.


Maternal bereavement and childhood asthma-analyses in two large samples of Swedish children.
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma. We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1-4 (n = 426,334) and 7-12 (n = 493,813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1-4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7-12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1-4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7-12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant. Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.


Genetic origin of lupus in NZB/SWR hybrids: lessons from an intercross study.
(SWR x NZB)F(1) (or SNF(1)) hybrid mice succumb to lupus nephritis. A previous analysis of SNF(1) x NZB backcross mice revealed the existence of 4 SWR loci (H2 on chromosome 17, Swrl-1 on chromosome 1, Swrl-2 on chromosome 14, and Swrl-3 on chromosome 18) and 2 NZB loci (Nba1 and Lbw2/Sbw2, both on chromosome 4). A second study focusing on SNF(1) x SWR backcross offspring uncovered 5 suggestive loci for antinuclear antibody formation, consisting of 3 dominant NZB contributions (Nba4 on chromosome 5, Lbw4 on chromosome 6, and Nba5 on chromosome 7) and 2 recessive SWR contributions (Swrl-1 on chromosome 1 and Swrl-4 on chromosome 10). The present intercross study was executed to replicate the earlier findings, using an independent panel of (SWR x NZB)F(2) offspring. A panel of (NZB x SWR)F(2) hybrids were phenotyped (for renal disease, early mortality, and a variety of autoantibodies) and genotyped (using 95 microsatellite primers positioned across all 19 autosomes and the X chromosome). Linkage analysis was conducted using the derived phenotype and genotype data, with the interval-mapping program MapManager. Four suggestive loci were mapped: Swrl-5 on chromosome 1 (peak at 106 cM), linked to hypergammaglobulinemia; an NZB locus on chromosome 5 (Nba4; peak at 15 cM), linked to IgG anti-single-stranded DNA (anti-ssDNA) antibodies, IgG anti-doubled-stranded DNA (anti-dsDNA) antibodies, and glomerulonephritis; an NZB locus on chromosome 13 (Nba6; peak at 28 cM), linked to IgG anti-dsDNA antibodies; and an SWR locus on chromosome 14 (Swrl-2; peak at 30 cM), linked to IgG anti-ssDNA antibodies. Eight additional loci revealed linkage at P < 0.01, of which 7 co-mapped with lupus susceptibility loci previously identified in other models. Considering all 3 mapping studies together, lupus in SWR/NZB hybrids appears to be the epistatic end product of several distinct loci, of which 3 SWR-derived loci (Swrl-1, Swrl-2, and Swrl-3) and 5 NZB-derived loci (Nba1, Nba3, Nba4, Nba5, and Lbw4) have been independently confirmed. The immunologic functions and molecular identities of these loci await elucidation.


Diabetic choroidopathy: a review of the current literature.
Diabetic retinopathy is an increasingly prevalent disease, and a leading contributor to the burden of all-cause blindness worldwide. In addition to retinal changes, choroidal abnormalities are common in patients with diabetes. The first studies concerning this vascular structure were based on histologic, indocyanine angiography and laser Doppler flowmetry techniques, but the development of new optical coherence tomography (OCT) technologies and imaging software for enhanced depth imaging (EDI)-OCT in recent years has made it possible to provide more detailed images of the choroidal anatomy and topography.In diabetic patients, several choroidal changes have been described in the literature throughout the years; the recent focus is choroidal thickness, which is significantly different from that in healthy patients. However, understanding choroidal manifestations of diabetic eye disease remains a real challenge, and this gap is hindering efforts towards better defining choroidal evaluation as a predictive factor for disease evolution and treatment response.This review aims to summarize the recent literature concerning changes in choroidal structure in diabetic patients, the relationship to diabetic retinal disease progression, and finally, the current and potential application of the measurement of variations in choroidal thickness for patient management.


In search of multimodal neuroimaging biomarkers of cognitive deficits in schizophrenia.
The cognitive deficits of schizophrenia are largely resistant to current treatments and thus are a lifelong illness burden. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) provides a reliable and valid assessment of cognition across major cognitive domains; however, the multimodal brain alterations specifically associated with MCCB in schizophrenia have not been examined. The interrelationships between MCCB and the abnormalities seen in three types of neuroimaging-derived maps-fractional amplitude of low-frequency fluctuations (fALFF) from resting-state functional magnetic resonance imaging (MRI), gray matter (GM) density from structural MRI, and fractional anisotropy from diffusion MRI-were investigated by using multiset canonical correlation analysis in data from 47 schizophrenia patients treated with antipsychotic medications and 50 age-matched healthy control subjects. One multimodal component (canonical variant 8) was identified as both group differentiating and significantly correlated with the MCCB composite. It demonstrated 1) increased cognitive performance associated with higher fALFF (intensity of regional spontaneous brain activity) and higher GM volumes in thalamus, striatum, hippocampus, and the mid-occipital region, with co-occurring fractional anisotropy changes in superior longitudinal fascicules, anterior thalamic radiation, and forceps major; 2) higher fALFF but lower GM volume in dorsolateral prefrontal cortex related to worse cognition in schizophrenia; and 3) distinct domains of MCCB might exhibit dissociable multimodal signatures, e.g., increased fALFF in inferior parietal lobule particularly correlated with decreased social cognition. Medication dose did not relate to these findings in schizophrenia. Our results suggest linked functional and structural deficits in distributed cortico-striato-thalamic circuits may be closely related to MCCB-measured cognitive impairments in schizophrenia.


Intron-loss evolution of hatching enzyme genes in Teleostei.
Hatching enzyme, belonging to the astacin metallo-protease family, digests egg envelope at embryo hatching. Orthologous genes of the enzyme are found in all vertebrate genomes. Recently, we found that exon-intron structures of the genes were conserved among tetrapods, while the genes of teleosts frequently lost their introns. Occurrence of such intron losses in teleostean hatching enzyme genes is an uncommon evolutionary event, as most eukaryotic genes are generally known to be interrupted by introns and the intron insertion sites are conserved from species to species. Here, we report on extensive studies of the exon-intron structures of teleostean hatching enzyme genes for insight into how and why introns were lost during evolution. We investigated the evolutionary pathway of intron-losses in hatching enzyme genes of 27 species of Teleostei. Hatching enzyme genes of basal teleosts are of only one type, which conserves the 9-exon-8-intron structure of an assumed ancestor. On the other hand, otocephalans and euteleosts possess two types of hatching enzyme genes, suggesting a gene duplication event in the common ancestor of otocephalans and euteleosts. The duplicated genes were classified into two clades, clades I and II, based on phylogenetic analysis. In otocephalans and euteleosts, clade I genes developed a phylogeny-specific structure, such as an 8-exon-7-intron, 5-exon-4-intron, 4-exon-3-intron or intron-less structure. In contrast to the clade I genes, the structures of clade II genes were relatively stable in their configuration, and were similar to that of the ancestral genes. Expression analyses revealed that hatching enzyme genes were high-expression genes, when compared to that of housekeeping genes. When expression levels were compared between clade I and II genes, clade I genes tends to be expressed more highly than clade II genes. Hatching enzyme genes evolved to lose their introns, and the intron-loss events occurred at the specific points of teleostean phylogeny. We propose that the high-expression hatching enzyme genes frequently lost their introns during the evolution of teleosts, while the low-expression genes maintained the exon-intron structure of the ancestral gene.


Never the twain? Reconciling national suicide prevention strategies with the practice, educational, and policy needs of mental health nurses (Part one).
Suicide remains as a distinct global public health problem, and the reduction of rates continues to be a major concern of the governments of many countries; this has given rise to the creation of national suicide prevention strategies. As with any other mental health-related policy document, it behoves mental health nurses to juxtapose these against the realities of their practice and educational needs. To this end, this two part paper draws on national suicide prevention strategy policy directions that appear to speak directly to the practice and/or educational needs of mental health nurses and critiques these. The direction indicating more training in risk assessment is perhaps questionable given that this is already by far the most developed area of the suicidology-focused literature and that our increased knowledge has risk factors that have not so far produced widespread reductions in suicide rates. Furthermore, this additional attention, at least in part, reflects the clear move towards more coercion and control in international mental health policy. The direction indicating that practitioners should use evidence-based interventions to prevent suicide is laudable although difficult to reconcile with practice realities given that there is currently a distinct lack of evidence-based interventions for working with people who are suicidal. As a result, this paper offers some suggested amendments to the national suicide prevention strategies, and the second part of this paper focuses on three more policy directions.


Purification of lysozyme using ultrafiltration.
This article examines the separation of lysozyme from chicken egg white by ultrafiltration with 25 kDa and 50 kDa MWCO polysulfone membranes. The effects of pH, system hydrodynamics, feed concentration, and transmembrane pressure on permeate flux, lysozyme transmission, purification factor, and productivity have been discussed. With both types of membranes, higher permeate flux and lysozyme transmission were observed at higher pH. Higher lysozyme purity was generally obtained with the 25 kDa MWCO membrane. Purity of lysozyme decreased when the feed concentration was increased. With the 50 kDa MWCO membrane permeate flux, productivity and the purity of lysozyme were found to increase with increase in transmembrane pressure. The possibility of using a two-step ultrafiltration process for achieving high productivity along with high purity of lysozyme was also investigated.


Young's type interference for probing the mode symmetry in photonic structures.
A revisited realization of the Young's double slit experiment is introduced to directly probe the photonic mode symmetry by photoluminescence experiments. We experimentally measure the far field angular emission pattern of quantum dots embedded in photonic molecules. The experimental data well agree with predictions from Young's interference and numerical simulations. Moreover, the vectorial nature of photonic eigenmodes results in a rather complicated parity property for different polarizations, a feature which has no counterpart in quantum mechanics.


Pupillary Reflex for Evaluation of Thoracic Paravertebral Block: A Prospective Observational Feasibility Study.
Although thoracic paravertebral block (TPVB) is recommended in major breast surgery, there is no gold standard to assess the success of TPVB. Pupillary dilation reflex (PDR) is the variation of the pupillary diameter after a noxious stimulus. The objective was to evaluate the feasibility of recording the PDR to assess analgesia in an anesthetized thoracic dermatome after TPVB. This prospective, observational, single-center study included 32 patients requiring breast surgery under general anesthesia and TPVB. TPVB was performed before surgery under ultrasound guidance with 20 mL of 0.75% ropivacaine. At the end of the surgery, remifentanil was stopped and the PDR was recorded after a 5-second tetanic stimulation (60 mA, 100 Hz) applied to the anterior chest wall. The PDR was defined as the maximal increase in pupil diameter after a standardized noxious stimulus, expressed as a percentage of the initial pupil diameter. The PDR was recorded twice in the same eye for each patient after a stimulus on both the TPVB and the control sides. Postoperative pain scores were recorded in a postanesthesia care unit. The primary outcome was the difference between the PDR on the TPVB and the control sides. The median (interquartile range) PDR was 9% (4%-13%) on the TPVB side and 41% (27%-66%) on the control side. There was a significant difference in the PDR between the TPVB and the control sides with a Hodges-Lehmann estimate of absolute difference of 37% points (95% confidence interval, 25-52, P < .001). Median postoperative pain scores (interquartile range) in the postanesthesia care unit were 1 (0-3) at rest and 1 (0-3) during mobilization, respectively. There was a linear correlation between maximal postoperative pain scores and the PDR on the TPVB side with a Pearson's correlation coefficient r = 0.40 (95% confidence interval, 0.06-0.66, P = .02). No correlation was found between the number of blocked dermatomes and maximal postoperative pain scores (P = .06) or between the number of blocked dermatomes and the PDR on the TPVB side (P = .15). This proof-of-concept trial suggests that the effect of TPVB could be monitored by measuring the PDR after anterior chest wall stimulation in the dermatome of interest.


[Opinion of parents and caregivers of interned children about their presence during the realization of invasive procedures].
The presence of family members during procedures is a controversial topic. Despite the widespread perception of its benefits, procedures are often carried out in places with restricted access. 1. To know parent s and caregiver s opinion about their presence during the performance of invasive procedures. 2. To determine the reasons to justify or deny their presence. Materials and methods. parents and caregivers of children admited to Hospital Municipal Materno Infantil de San Isidro "Dr. Carlos Gianantonio" and Sanatorio "Mater Dei". transversal study. Anonymous survey. One hundred and seventy eight surveys were delivered and 172 were recovered. The average age of respondents was 33.75 years, 80.81% were women, 98.84% had children. The relationship to the patient: mother 70.93%, father 18.02%, grandparents 6.4%, uncle 2.33% and sibling 2.33%. The desire to be present at the different procedures was always greater than 50%. There is an inverse relationship with the invasiveness of the procedure: endovenous access 88.95%, laceration repair (sutures) 78.49%, lumbar puncture 73.84%, endotracheal intubation 56.98% and cardiopul-monary resuscitation 58.72%. Similar results were obtained for unconscious child. The most frequently reasons to justify the presence are emotional containment of the child and procedure monitoring. 1) The majority of respondents wanted to be present. 2) There is an inverse relationship between the desire of the family and level of invasiveness. 3) There are not significant differences comparing conscious or unconscious child.


Molecular evidence for SARS-CoV-2 in samples collected from patients with morbilliform eruptions since late 2019 in Lombardy, northern Italy.
As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like syndromes, providing preliminary evidence for undetected early circulation of SARS-CoV-2. Overall, 435 samples from 156 cases were investigated. RNA from oropharyngeal swabs (N = 148) and urine (N = 141) was screened with four hemi-nested PCRs and molecular evidence for SARS-CoV-2 infection was found in 13 subjects. Two of the positive patients were from the pandemic period (2/12, 16.7%, March 2020-March 2021) and 11 were from the pre-pandemic period (11/44, 25%, August 2019-February 2020). Sera (N = 146) were tested for anti-SARS-CoV-2 IgG, IgM, and IgA antibodies. Five of the RNA-positive individuals also had detectable anti-SARS-CoV-2 antibodies. No strong evidence of infection was found in samples collected between August 2018 and July 2019 from 100 patients. The earliest sample with evidence of SARS-CoV-2 RNA was from September 12, 2019, and the positive patient was also positive for anti-SARS-CoV-2 antibodies (IgG and IgM). Mutations typical of B.1 strains previously reported to have emerged in January 2020 (C3037T, C14408T, and A23403G), were identified in samples collected as early as October 2019 in Lombardy. One of these mutations (C14408T) was also identified among sequences downloaded from public databases that were obtained by others from samples collected in Brazil in November 2019. We conclude that a SARS-CoV-2 progenitor capable of producing a measles-like syndrome may have emerged in late June-late July 2019 and that viruses with mutations characterizing B.1 strain may have been spreading globally before the first Wuhan outbreak. Our findings should be complemented by high-throughput sequencing to obtain additional sequence information. We highlight the importance of retrospective surveillance studies in understanding the early dynamics of COVID-19 spread and we encourage other groups to perform retrospective investigations to seek confirmatory proofs of early SARS-CoV-2 circulation.


Greb1 is required for axial elongation and segmentation in vertebrate embryos.
During vertebrate embryonic development, the formation of axial structures is driven by a population of stem-like cells that reside in a region of the tailbud called the chordoneural hinge (CNH). We have compared the mouse CNH transcriptome with those of surrounding tissues and shown that the CNH and tailbud mesoderm are transcriptionally similar, and distinct from the presomitic mesoderm. Amongst CNH-enriched genes are several that are required for axial elongation, including Wnt3a, Cdx2, Brachyury/T and Fgf8, and androgen/oestrogen receptor nuclear signalling components such as Greb1 We show that the pattern and duration of tailbud Greb1 expression is conserved in mouse, zebrafish and chicken embryos, and that Greb1 is required for axial elongation and somitogenesis in zebrafish embryos. The axial truncation phenotype of Greb1 morphant embryos can be explained by much reduced expression of No tail (Ntl/Brachyury), which is required for axial progenitor maintenance. Posterior segmentation defects in the morphants (including misexpression of genes such as mespb, myoD and papC) appear to result, in part, from lost expression of the segmentation clock gene, her7.


Bevacizumab plus docetaxel and cisplatin for metastatic breast cancer: a pilot phase II study.
Bevacizumab is a monoclonal antibody that prevents angiogenesis by inhibiting vascular endothelial growth factor (VEGF) activity. Clinically, it has been used to treat a diverse range of cancer types. In this pilot phase II study, we investigated the efficacy and safety profiles of bevacizumab in combination with docetaxel plus cisplatin for patients with advanced HER2-negative metastatic breast cancer. Between 2005 and 2008, 20 patients with advanced breast cancer were recruited from the Taipei Medical University Hospital. Bevacizumab was administered every two weeks in a 12-cycle treatment with docetaxel plus cisplatin. The primary end-point for this study was the overall response rate. The secondary end-points were progression-free survival and the safety profiles of the combined therapy. The average number of treatment cycles was 10.5 with a response rate of 80%. Neutropenia and neuropathy were the most commonly observed adverse events. Seven patients achieved complete remission and nine patients achieved partial remission. For the overall patient group in this study, the median time-to-progression and overall survival were 28.0 weeks and 52 weeks, respectively. The median time-to-progression and overall survival for the 10 patients that completed all 12 cycles of treatment were 64.0 weeks and 80 weeks, respectively. In one patient, a very rapid reduction in the level of breast cancer lung metastases was observed one week post-treatment. Based on this pilot study, bevacizumab in combination with docetaxel and cisplatin is likely to be an effective treatment option for metastatic breast cancer that warrants further study.


Asymmetries of the balanced SSFP profile. Part II: white matter.
The signal profile measured in balanced steady-state free precession has been shown to exhibit tissue-dependent asymmetries that were hypothesized to relate to properties of the tissue microenvironment. It was proposed that balanced steady-state free precession asymmetry may reflect subtle features of the frequency distribution in tissue. The present work investigates the large balanced steady-state free precession asymmetries observed in white matter. First, maps quantifying the asymmetry are presented, which demonstrate considerable heterogeneity within white matter, with some tracts exhibiting significant asymmetry and others having a nearly symmetric profile. These maps are compared with a diffusion-tensor atlas and indicate that the highest asymmetry is found in tracts oriented perpendicular to the main magnetic field. Measurements conducted at multiple repetition times suggest that the asymmetries are characterized by relatively small frequency shifts. These results are discussed in the context of previous work studying gradient-recalled echo (GRE) signal behavior in white matter, and it is suggested that these two techniques are detecting closely related phenomena.


Eukaryotic Argonautes come into focus.
Despite the fact that different classes of small RNAs are generated by largely different biogenesis pathways, all mature small RNAs associate with an Argonaute family member to form the RNA-induced silencing complex (RISC). Gene silencing by RISC could not be studied in molecular detail because structural information on eukaryotic Argonautes was lacking. Recently, however, the structure of human Argonaute-2 (hAgo2), a model for RISC function, was determined in complexes with heterogeneous guide RNA and in complexes with a specific miRNA. We review the exciting advances that these two structures, together with the structure of a budding yeast Argonaute, brought to the field of eukaryotic RNA interference (RNAi), and how they will enable a more detailed mechanistic understanding of eukaryotic RISC.


The mevalonate pathway controls heart formation in Drosophila by isoprenylation of Ggamma1.
The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. A screen for genes that control Drosophila heart development revealed a cardiac defect in which pericardial and cardial cells dissociate, which causes loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in the genes encoding HMG-CoA reductase, downstream enzymes in the mevalonate pathway, and G protein Ggamma1, which is geranylgeranylated, thus representing an end point of isoprenoid biosynthesis. Our findings reveal a cardial cell-autonomous requirement of Ggamma1 geranylgeranylation for heart formation and suggest the involvement of the mevalonate pathway in congenital heart disease.