Evolution of ventricular function in children with permanent right ventricular pacing after tetralogy of Fallot repair: A midterm follow-up.
We aim to evaluate the midterm effect of chronic apical right ventricular (RV) pacing on right and left ventricular (LV) function using different modalities of echocardiography including conventional echocardiography, tissue Doppler imaging and two-dimension speckle tracking echocardiography. This case-control study enrolled 49 patients divided into two groups: a paced group and a nonpaced group. The paced group included 23 patients that underwent tetralogy of Fallot (TOF) repair and required permanent pacemaker insertion for postoperative complete heart block. The nonpaced group included 26 patients that had TOF repair at the same period. The median age for the paced and nonpaced groups was 6 and 8 years, respectively (P = .169). The follow-up duration after TOF surgical repair was 4 years for the paced patients and 5 years for nonpaced patients (P = .411). In the nonpaced group, the QRS duration increased and LV global longitudinal strain (GLS) decreased significantly with increasing duration after TOF repair, P value was .006 and .042, respectively. In the paced group, tricuspid annular systolic plane excursion (TAPSE) was significantly correlated with age (r = .578; P = .004) and duration following TOF correction (r = .724; P < .001). Chronic RV apical pacing in children after TOF repair was associated with better clinical status, preservation of RV systolic function, and prevention of progressive QRS prolongation. RV pacing was not associated with progressive deterioration of LV systolic function with increasing the time interval following TOF repair. Therefore, RV pacing can be beneficial in corrected TOF patients presenting with RV failure.


Evaluation of fetal echocardiography as a routine antenatal screening tool for detection of congenital heart disease.
Fetal echocardiography plays a pivotal role in identifying the congenital heart defects (CHDs) in utero. Though foetal echocardiography is mostly reserved for high risk pregnant women, its role as a routine prenatal screening tool still needs to be defined. Performing foetal echocardiography based on only these indications can lead to a significant numbers of CHD cases going undetected who will be deprived of further management leading to increased early neonatal mortalities. The aim of this study is to assess the incidence of CHDs by fetal echocardiography in an unselected population of pregnant women in comparison with pregnant women with conventional high risk factors for CHD. This study enrolled consecutive pregnant women who attended antenatal clinic between 2008 and 2012 in a tertiary care hospital. These pregnant women were categorized into two groups: high risk group included pregnant women with traditional risk factors for CHD as laid down by Pediatric Council of the American Society of Echocardiography and low risk group. Detailed fetal 2 D echocardiography was done. A total of 1,280 pregnant women were included in study. The 118 women were categorized as the high risk group while remaining 1,162 were included in the low risk group. Twenty six cases of CHDs were detected based on abnormal foetal echocardiography (20.3 per 1,000). Two of the 26 cases of CHD occurred in high risk group whereas the remaining 24 occurred in low risk pregnancy. The difference in the incidence of CHDs between the two groups was not significant statistically (P=0.76). Our study shows no difference in incidence of CHDs between pregnancies associated with high risk factors compared to low risk pregnancies. So we advocate foetal echocardiography should be included as a part of routine antenatal screening and all pregnant women irrespective of risk factors for CHDs.


Incidence and severity of postoperative pain following routine placement of amalgam restorations.
This study investigated the incidence and severity of postoperative sensitivity, examining several potential sources of pain. One hundred eighteen subjects were asked about pain that they experienced following an appointment for restoration of a moderate Class I or II carious lesion. The survey required subjects to complete 3 questionnaires, 1, 4, and 7 days posttreatment. Questions covered 9 different potential sources of postoperative pain and the use of pain medication following the dental appointment. A great majority of subjects experienced postoperative pain from at least 1 source, and approximately half of those who reported pain following the appointment found it necessary to take medication for relief. For almost all categories, the level of pain reported at 4 and 7 days was substantially less than that reported after 24 hours. Patients commonly experience pain in the first 24 hours after operative treatment. Dentists should consider recommending that patients who are likely to experience postoperative pain take a nonprescription analgesic around the time of the treatment and for 24 hours afterward to prevent discomfort.


The Real-World Global Use of Patient-Reported Outcomes for the Care of Patients With Inflammatory Bowel Disease.
Many patient-reported outcomes (PROs) have been developed for inflammatory bowel disease (IBD) without recommendations for clinical use. PROs differ from physician-reported disease activity indices; they assess patients' perceptions of their symptoms, functional status, mental health, and quality of life, among other areas. We sought to investigate the current global use and barriers to using PROs in clinical practice for IBD. A cross-sectional survey was performed. An electronic questionnaire was sent to an international group of providers who care for patients with IBD. There were 194 respondents, including adult/pediatric gastroenterologists, advanced practice providers, and colorectal surgeons from 5 continents. The majority (80%) use PROs in clinical practice, 65% frequently found value in routine use, and 50% frequently found PROs influenced management. Thirty-one different PROs for IBD were reportedly used. Barriers included not being familiar with PROs, not knowing how to incorporate PRO results into clinical practice, lack of electronic medical record integration, and time constraints. Most (91%) agreed it would be beneficial to have an accepted set of consistently used PROs. The majority (60%) thought that there should be some cultural differences in PROs used globally but that PROs for IBD should be consistent around the world. PROs are used frequently in clinical practice with wide variation in which are used and how they influence management. Education about PROs and how to use and interpret an accepted set of PROs would decrease barriers for use and allow for global harmonization.


Quantitative morphological signatures define local signaling networks regulating cell morphology.
Although classical genetic and biochemical approaches have identified hundreds of proteins that function in the dynamic remodeling of cell shape in response to upstream signals, there is currently little systems-level understanding of the organization and composition of signaling networks that regulate cell morphology. We have developed quantitative morphological profiling methods to systematically investigate the role of individual genes in the regulation of cell morphology in a fast, robust, and cost-efficient manner. We analyzed a compendium of quantitative morphological signatures and described the existence of local signaling networks that act to regulate cell protrusion, adhesion, and tension.


Impact of hydrothermal and mechanical processing on dissolution kinetics and rheology of oat β-glucan.
Oat mixed-linkage β-glucan has been shown to lower fasting blood cholesterol concentrations due notably to an increase in digesta viscosity in the proximal gut. To exert its action, the polysaccharide has to be released from the food matrix and hydrated. The dissolution kinetics of β-glucan from three oat materials, varying in their structure, composition and degree of processing, was investigated by incubating the oats at 37°C over multiple time points (up to 72h). The samples were analysed for β-glucan content, weight-average molecular weight and rheological behaviour. Regardless of the materials studied and the processing applied, the solubilisation of β-glucan was not complete. Mechanical and hydrothermal processing led to differences in the viscosity flow curves of the recovered solutions, with the presence of particulates having a marked effect. This study revealed that the structure and processing methods applied to oat materials resulted in varied and complex rheological properties, especially when particulates are present.


MS2 Virus-like Particles as a Versatile Peptide Presentation Platform: Insights into the Deterministic Abilities for Accommodating Heterologous Peptide Lengths.
Virus-like particles (VLPs) are nanostructures with the potential to present heterologous peptides at high density, thereby triggering heightened immunogenicity. RNA bacteriophage MS2 VLPs are a compelling delivery platform among them. However, a notable hurdle arises from the immune response toward MS2 coat protein, swiftly eliminating subsequent vaccinations via the same vector. Although larger inserts effectively mask carrier epitopes, current research predominantly focuses on displaying short conserved peptides (<30 aa). A systematic evaluation regarding the deterministic ability of MS2 VLPs as a platform for presenting heterologous peptides remains a gap. In light of this, we employed the "single-chain dimer" paradigm to scrutinize the tolerance of MS2 VLPs for peptide/protein insertions. The results unveiled functional MS2 VLP assembly solely for inserts smaller than 91 aa. Particularly noteworthy is the largest insertion achieved on the MS2 VLPs to date: the RNA helicase A (RHA) dsRNA-binding domains (dsRBD1). Attempts to introduce additional linkers or empty coat subunits fail to augment the expression level or assembly of the MS2 VLPs displaying dsRBD1, affirming 91 aa as the upper threshold for exogenous protein presentation. By illuminating the precise confines of MS2 VLPs in accommodating distinct peptide lengths, our study informs the selection of appropriate peptide and protein dimensions. This revelation not only underscores the scope of MS2 VLPs but also establishes a pivotal reference point, facilitating the strategic manipulation of MS2 VLPs to design next-generation epitope/antibody-based therapeutics.


Long-term colorectal-cancer incidence and mortality after lower endoscopy.
Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain. We examined the association of the use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal-cancer incidence (through June 2010) and colorectal-cancer mortality (through June 2012) among participants in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 88,902 participants followed over a period of 22 years, we documented 1815 incident colorectal cancers and 474 deaths from colorectal cancer. With endoscopy as compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.57 (95% confidence interval [CI], 0.45 to 0.72) after polypectomy, 0.60 (95% CI, 0.53 to 0.68) after negative sigmoidoscopy, and 0.44 (95% CI, 0.38 to 0.52) after negative colonoscopy. Negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate hazard ratio, 0.73; 95% CI, 0.57 to 0.92). Multivariate hazard ratios for death from colorectal cancer were 0.59 (95% CI, 0.45 to 0.76) after screening sigmoidoscopy and 0.32 (95% CI, 0.24 to 0.45) after screening colonoscopy. Reduced mortality from proximal colon cancer was observed after screening colonoscopy (multivariate hazard ratio, 0.47; 95% CI, 0.29 to 0.76) but not after sigmoidoscopy. As compared with colorectal cancers diagnosed in patients more than 5 years after colonoscopy or without any prior endoscopy, those diagnosed in patients within 5 years after colonoscopy were more likely to be characterized by the CpG island methylator phenotype (CIMP) (multivariate odds ratio, 2.19; 95% CI, 1.14 to 4.21) and microsatellite instability (multivariate odds ratio, 2.10; 95% CI, 1.10 to 4.02). Colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal-cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have CIMP and microsatellite instability. (Funded by the National Institutes of Health and others.).


Disorder-derived, strong tunneling attenuation in bis-phosphonate monolayers.
Monolayers of alkyl bisphosphonic acids (bisPAs) of various carbon chain lengths (C4, C8, C10, C12) were grown on aluminum oxide (AlO(x)) surfaces from solution. The structural and electrical properties of these self-assembled monolayers (SAMs) were compared with those of alkyl monophosphonic acids (monoPAs). Through contact angle (CA) and Kelvin-probe (KP) measurements, ellipsometry, and infrared (IR) and x-ray photoelectron (XPS) spectroscopies, it was found that bisPAs form monolayers that are relatively disordered compared to their monoPA analogs. Current-voltage (J-V) measurements made with a hanging Hg drop top contact show tunneling to be the prevailing transport mechanism. However, while the monoPAs have an observed decay constant within the typical range for dense monolayers, β(mono) = 0.85 ± 0.03 per carbon atom, a surprisingly high value, β(bis) = 1.40 ± 0.05 per carbon atom, was measured for the bisPAs. We attribute this to a strong contribution of 'through-space' tunneling, which derives from conformational disorder in the monolayer due to strong interactions of the distal phosphonic acid groups; they likely form a hydrogen-bonding network that largely determines the molecular layer structure. Since bisPA SAMs attenuate tunnel currents more effectively than do the corresponding monoPA SAMs, they may find future application as gate dielectric modification in organic thin film devices.


Metformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus.
Existing literature suggests that metformin, the most commonly used biguanide, may lower colorectal cancer risk. Because most colorectal cancers originate in precancerous adenomas, we examined whether metformin use lowered colorectal adenoma risk after polypectomy in patients with type-2 diabetes. Retrospective cohort study of 40- to 89-year-old Kaiser Permanente Northern California patients who had type 2 diabetes, and ≥1 adenoma detected at baseline colonoscopy during 2000 to 2009 and a repeat colonoscopy 1 to 10 years from baseline adenoma diagnosis through 2012. Cox models evaluated the association between metformin use during follow-up and subsequent adenoma diagnoses, controlling for age, race/ethnicity, sex, body mass index, and repeat examination indication. Study included 2,412 patients followed for a median of 4.5 years; cumulatively, 1,117 (46%) patients had ≥1 adenoma at repeat colonoscopy. Compared with patients not receiving diabetes medications (n = 1,578), metformin-only use (n = 457) was associated with lower adenoma recurrence risk [adjusted HR, 0.76; 95% confidence interval (CI), 0.65-0.89], and the association was stronger with increasing total metformin dose [quartile (Q) 1: HR, 0.90; 95% CI, 0.72-1.12; Q2: HR, 0.89; 95% CI, 0.70-1.12; Q3: HR, 0.80; 95% CI, 0.63-1.01; Q4: HR, 0.50; 95% CI, 0.42-0.60, Ptrend < 0.001]. Findings were unchanged in sensitivity analyses, including evaluating only outcomes during the 3- to 10-year period from baseline. Our study suggests a potential benefit of metformin use in lowering the risk of subsequent adenomas after polypectomy in patients with type 2 diabetes. Metformin may lower colorectal cancer risk by reducing the formation of precancerous lesions, reinforcing the potential additional benefits of its use.


The oral health status of America's rural children: An opportunity for policy change.
The purpose of our study was to examine the association between rurality and select oral health care metrics: teeth condition, decay, and access measures such as preventive dental care among children in the United States. We conducted a cross-sectional study with a sample of 20,842 respondents from the 2017 to 2018 National Survey of Children's Health (NSCH), a nationally representative sample of U.S. children. Socio-demographic information, residence, and oral health and healthcare utilization information were used to create study variables. Descriptive statistics, bivariate analyses, and a multivariable regression model were performed. Rural children were less likely to have a preventive dental visit than urban children (84.9 percent versus 87.5 percent, P = 0.03). Children residing in rural areas were more likely to have their teeth condition reported as fair or poor than children residing in urban areas (7.3 percent versus 6.6 percent, P = 0.02). Compared to their urban counterparts, rural children were also less likely to have received fluoride treatment (46.6 percent versus 52.5 percent, P = 0.0022) and less likely to have received a dental sealant (19.5 percent versus 22.5 percent, P = 0.0147). In adjusted analysis, there was no significant difference in receiving a preventive dental visit for rural children, compared to their urban counterparts. As preparations are made for the 2020 Surgeon General's report on oral health, the current study provides important evidence to inform future advocacy and legislative priorities. To reduce urban-rural disparities among children, there must be enhanced dental care access, dental workforce expansion, and increased awareness about preventive oral health services.


Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo.
Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and real-time in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivoIn silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients.IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.


Predicting the Binding Mode of 2-Hydroxypropyl-β-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory.
It has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin (HPβCD), has reasonable therapeutic effect on Niemann-Pick disease type C, which is caused by abnormal accumulation of unesterified cholesterol and glycolipids in the lysosomes and shortage of esterified cholesterol in other cellular compartments. We study the binding affinity and mode of HPβCD with cholesterol to elucidate the possible mechanism of HPβCD for removing cholesterol from the lysosomes. The dominant binding mode of HPβCD with cholesterol is found based on the molecular dynamics simulation and a statistical mechanics theory of liquids, or the three-dimensional reference interaction site model theory with Kovalenko-Hirata closure relation. We examine the two types of complexes between HPβCD and cholesterol, namely, one-to-one (1:1) and two-to-one (2:1). It is predicted that the 1:1 complex makes two or three types of stable binding mode in solution, in which the βCD ring tends to be located at the edge of the steroid skeleton. For the 2:1 complex, there are four different types of the complex conceivable, depending on the orientation between the two HPβCDs: head-to-head (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail (TT). The HT and HH cyclodextrin dimers show higher affinity to cholesterol compared to the other dimers and to all the binding modes of 1:1 complexes. The physical reason why the HT and HH dimers have higher affinity compared to the other complexes is discussed based on the consistency with the 1:1 complex. On the one hand, in case of the HT and HH dimers, the position of each CD in the dimer along the cholesterol chain comes right on or close to one of the positions where a single CD makes a stable complex. On the other hand, one of the CD molecules is located on unstable region along the cholesterol chain, for the case of TH and TT dimers.


Energetic charged particles in the uranian magnetosphere.
During the encounter with Uranus, the cosmic ray system on Voyager 2 measured significant fluxes of energetic electrons and protons in the regions of the planets magnetosphere where these particles could be stably trapped. The radial distribution of electrons with energies of megaelectron volts is strongly modulated by the sweeping effects ofthe three major inner satellites Miranda, Ariel, and Umbriel. The phase space density gradient of these electrons indicates that they are diffusing radially inward from a source in the outer magnetosphere or magnetotail. Differences in the energy spectra of protons having energies of approximately 1 to 8 megaelectron volts from two different directions indicate a strong dependence on pitch angle. From the locations of the absorption signatures observed in the electron flux, a centered dipole model for the magnetic field of Uranus with a tilt of 60.1 degrees has been derived, and a rotation period of the planet of 17.4 hours has also been calculated. This model provides independent confirmaton of more precise determinations made by other Voyager experiments.


The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis.
In order to examine the spatial organisation of stem cells and their progeny in human epidermis, we developed a method for whole-mount epidermal immunofluorescence labelling using high surface beta1 integrin expression as a stem cell marker. We confirmed that there are clusters of high beta1 integrin-expressing cells at the tips of the dermal papillae in epidermis from several body sites, whereas alpha6 integrin expression is more uniform. The majority of actively cycling cells detected by Ki67 or bromodeoxyuridine labelling were found in the beta1 integrin-dull, transit amplifying population and integrin-negative, keratin 10-positive cells left the basal layer exclusively from this compartment. When we examined p53-positive clones in sun-exposed epidermis, we found two types of clone that differed in size and position in a way that was consistent with the founder cell being a stem or transit amplifying cell. The patterning of the basal layer implies that transit amplifying cells migrate over the basement membrane away from the stem cell clusters. In support of this, isolated beta1 integrin-dull keratinocytes were more motile on type IV collagen than beta1 integrin-bright keratinocytes and EGFP-labelled stem cell clones in confluent cultured sheets were compact, whereas transit amplifying clones were dispersed. The combination of whole-mount labelling and lineage marking thus reveals features of epidermal organisation that were previously unrecognised.


Zoonotic cutaneous leishmaniasis in central Tunisia: spatio temporal dynamics.
Zoonotic cutaneous leishmaniasis (ZCL) is endemic in many rural areas of the Southern and Eastern Mediterranean region where different transmission patterns of the disease have been described. This study was carried out in a region located in Central Tunisia and aimed to investigate the spatio-temporal dynamics of the disease from 1999 to 2004. Incident ZCL cases were defined by clinical diagnosis, confirmed by a positive skin test and/or parasitological examination. Annual ZCL rates were calculated for 94 regional sectors that comprise the study region of Sidi-Bouzid. Spatial and temporal homogeneity were initially investigated by chi-squared tests. Next, spatial scan statistics were used to identify spatial, temporal and spatio-temporal clusters that display abnormally high incidence rates. A hierarchical Bayesian Poisson regression model with spatial effects was fitted to signify explanatory socio-geographic factors related to spatial rate variability. Temporal ZCL dynamics for the 94 sectors were described via a linear mixed model. A total of 15 897 ZCL cases were reported in the 6-year study period, with an annual incidence rate of 669.7/100 000. An outbreak of the disease was detected in 2004 (1114/100 000). Spatial clustering is evident for the whole time period. The most likely cluster according to the spatial scan statistic, contains seven sectors with abnormally high incidence rates and approximately 5% of the total population. ZCL rates per sector are mostly related to the urban/rural index; sectoral population density and the number of inhabitants per household do not appear to contribute much to the explanation of rate variability. The dynamics of the disease within the study period are satisfactorily described by quadratic curves that differ for urban and rural areas. ZCL rates vary across space and time; rural/urban areas and environmental factors may explain part of this variation. In the study region, the Sidi Saâd dam-constructed in the early eighties and identified by previous studies as a major reason for the first outbreak of the disease-seems to be still related to increased ZCL rates. The most likely spatial cluster of high incidence rates contains regions located close to the dam. Our findings of increased incidences in urban areas support the hypothesis of increased incidences in peri-urban environments due to changes in sandfly/rodent living habits over recent years.


Identifying the provenance of Leach's storm petrels in the North Atlantic using polychlorinated biphenyl signatures derived from comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry.
PCB signatures can be used for source identification, exposure studies, age dating and bio-monitoring. This study uses comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry (GCxGC-ToFMS) to produce a PCB signature comprised of over 80 PCBs for individual Leach's storm petrels (Oceanodroma leucorhoa). The Leach's storm petrel is a relatively small, elusive, understudied pelagic bird, which only returns to remote islands under darkness during the breeding season. Samples were obtained from 25 Leach's storm petrels found dead in Canada and the UK following storm events in 2006 and 2009. Tissue samples were extracted and analysed by GCxGC-ToFMS and results showed that 83 PCB congeners were present in >60% of samples. An assessment of the PCB signature in four different tissue types showed that it did not vary greatly in samples obtained from the gut, heart, liver and stomach. Multivariate statistical analysis identified a distinctive PCB signature in birds from Canada and Europe which was used to identify the regional provenance and transatlantic movement of individual birds. The findings showcase the ability of GCxGC-ToFMS to provide the high quality congener specific analysis that is necessary for PCB fingerprinting, as well as highlighting the potential of PCB signatures for use in ecological studies of movement, foraging and behaviour.


Impacts of human activities on distribution of sulfate-reducing prokaryotes and antibiotic resistance genes in marine coastal sediments of Hong Kong.
Sulfate-reducing prokaryotes (SRPs) and antibiotic resistance genes (ARGs) in sediments could be biomarkers for evaluating the environmental impacts of human activities, although factors governing their distribution are not clear yet. By using metagenomic approach, this study investigated the distributions of SRPs and ARGs in marine sediments collected from 12 different coastal locations of Hong Kong, which exhibited different pollution levels and were classified into two groups based on sediment parameters. Our results showed that relative abundances of major SRP genera to total prokaryotes were consistently lower in the more seriously polluted sediments (P-value < 0.05 in 13 of 20 genera), indicating that the relative abundance of SRPs is a negatively correlated biomarker for evaluating human impacts. Moreover, a unimodel distribution pattern for SRPs along with the pollution gradient was observed. Although total ARGs were enriched in sediments from the polluted sites, distribution of single major ARG types could be explained neither by individual sediment parameters nor by corresponding concentration of antibiotics. It supports the hypothesis that the persistence of ARGs in sediments may not need the selection of antibiotics. In summary, our study provided important hints of the niche differentiation of SRPs and behavior of ARGs in marine coastal sediment.


Inhibition of dengue virus polymerase by blocking of the RNA tunnel.
Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Neither vaccine nor antiviral therapy is currently available for DENV. We report here that N-sulfonylanthranilic acid derivatives are allosteric inhibitors of DENV RNA-dependent RNA polymerase (RdRp). The inhibitor was identified through high-throughput screening of one million compounds using a primer extension-based RdRp assay [substrate poly(C)/oligo(G)(20)]. Chemical modification of the initial "hit" improved the compound potency to an IC(50) (that is, a concentration that inhibits 50% RdRp activity) of 0.7 microM. In addition to suppressing the primer extension-based RNA elongation, the compound also inhibited de novo RNA synthesis using a DENV subgenomic RNA, but at a lower potency (IC(50) of 5 microM). Remarkably, the observed anti-polymerase activity is specific to DENV RdRp; the compound did not inhibit WNV RdRp and exhibited IC(50)s of >100 microM against hepatitis C virus RdRp and human DNA polymerase alpha and beta. UV cross-linking and mass spectrometric analysis showed that a photoreactive inhibitor could be cross-linked to Met343 within the RdRp domain of DENV NS5. On the crystal structure of DENV RdRp, Met343 is located at the entrance of RNA template tunnel. Biochemical experiments showed that the order of addition of RNA template and inhibitor during the assembly of RdRp reaction affected compound potency. Collectively, the results indicate that the compound inhibits RdRp through blocking the RNA tunnel. This study has provided direct evidence to support the hypothesis that allosteric pockets from flavivirus RdRp could be targeted for antiviral development.


Serum Anti-Müllerian Hormone Levels in Precocious Puberty Girls according to Stage of GnRH Agonist Treatment.
Few studies have investigated the long-term effects of gonadotropin-releasing hormone (GnRH) agonist treatment on the reproductive function of central precocious puberty (CPP) girls. In this cross-sectional study, we assessed the ovarian function by analyzing the serum anti-Müllerian hormone (AMH) levels of CPP girls. Our study included 505 CPP girls subdivided into 5 groups according to the GnRH agonist treatment stage: group A (before treatment, n = 98), group B (3 months after initiation, n = 103), group C (12 months after initiation, n = 101), group D (24 months after initiation, n = 101), and group E (6 months after discontinuation, n = 102). We compared the serum AMH levels of the CPP girls with those of 100 bone age-matched controls (before treatment: n = 55; after discontinuation: n = 45). At baseline, the mean AMH level of the CPP girls was 5.9 ± 3.6 ng/mL. The mean AMH level after 3 months of the GnRH agonist treatment was lower (4.7 ± 3.2 ng/mL, P = 0.047) than that at baseline and recovered after 12 months of treatment. Six months after discontinuation, the AMH levels were similar to those at pre-treatment. Before and after the GnRH agonist treatment, the AMH levels were similar to those of the bone age-matched controls. In the precocious puberty girls, the AMH levels based on the GnRH agonist treatment stage were all within the normal reference range. The results of this study suggest that GnRH agonist treatment has no adverse effects on the reproductive function.


Patients' wishes, pregnancy and vascular access: When one size does not fit all.
Pregnancy in dialysis patients is a rare but important event that challenges our knowledge and demands re-thinking many aspects of our practice, including vascular access. This editorial briefly discusses some open questions on vascular access in this situation that challenge the motto 'fistula first' and underline the need for personalised approaches. Information on vascular access in pregnant women is scant. Different approaches may be considered between women on dialysis already on a well-functioning tunnelled catheter and newly placed catheters: while a tunnelled catheter in a woman already stabilised on outpatient dialysis, who has shown being able to take correct care of it and who has freely chosen this option, is a reasonable choice, central venous catheters placed during pregnancy, especially in the hospital setting, may have a high risk of complications. Conversely, pregnancy may increase the risk of development of fistula aneurysms, but the frequency of this complication is still unknown. The problem of whether or not shifting pregnant patients on peritoneal dialysis to daily haemodialysis sessions is still open, as well as the role of patients' preference for avoidance of an invasive procedure, or refuse of pain. In the wait for answers, reflecting on the problems encountered by pregnant women on dialysis should make us reflect on how to improve vascular access management for all our patients.


Sexual violence and associated factors among women in HIV discordant and concordant relationships in Uganda.
HIV serodiscordance is a sexual partnership in which one partner is infected with HIV while the other is not. Managing emotional and sexual intimacy in HIV serodiscordant unions can be difficult due to concerns about HIV transmission and the challenge of initiating and maintaining safe sex. In situations where couples are jointly aware of their HIV status, women in serodiscordant unions may face increased risk of partner violence. We conducted an investigation to assess risk factors for HIV serodiscordance and determine if HIV serodiscordance is associated with incident sexual violence among a cohort of women attending HIV post-test club services at three AIDS Information Centers (AICs) in Uganda. Using a prospective study of 250 women, we elicited information about sexual violence using structured face-to-face interviews. Sexual violence and risk factors were assessed and compared among HIV positive women in HIV discordant unions, HIV negative women in discordant unions, and HIV negative women in negative concordant unions. Multivariable logistic regression was used to assess the association between participants' serostatus and sexual violence. HIV negative women in serodiscordant relationships (36.1±11.1 years, range: 19-65 years) were significantly older than either HIV positive women in serodiscordant relationships (32.2±9.0 years, range: 18-56 years), or HIV negative women in concordant relationships (32.3±11.0 years, range: 18-62), (p=0.033). Early age at sexual debut was associated with a 2.4-fold increased risk of experiencing sexual violence (OR 2.4, 95% CI 1.27-4.65). Based on unadjusted analysis, HIV positive women in discordant relationship were at highest risk for sexual violence compared to HIV negative women in discordant unions, and HIV negative women in negative concordant unions. HIV negative women in discordant relationships and those in concordant negative relationships showed no increased risk for sexual violence. However, couples' HIV serostatus was not significant related to incident sexual violence after controlling for potential confounding covariates. Nevertheless, the results were able to elucidate the sexual violence risk factor profile of participants based on couples' HIV serostatus. Couple counseling protocols at HIV voluntary counseling and testing centers in Uganda should identify those at risk for sexual violence and develop interventions to reduce its incidence.


Biases in the perception of self-motion during whole-body acceleration and deceleration.
Several studies have investigated whether vestibular signals can be processed to determine the magnitude of passive body motions. Many of them required subjects to report their perceived displacements offline, i.e., after being submitted to passive displacements. Here, we used a protocol that allowed us to complement these results by asking subjects to report their introspective estimation of their displacement continuously, i.e., during the ongoing body rotation. To this end, participants rotated the handle of a manipulandum around a vertical axis to indicate their perceived change of angular position in space at the same time as they were passively rotated in the dark. The rotation acceleration (Acc) and deceleration (Dec) lasted either 1.5 s (peak of 60°/s(2), referred to as being "High") or 3 s (peak of 33°/s(2), referred to as being "Low"). The participants were rotated either counter-clockwise or clockwise, and all combinations of acceleration and deceleration were tested (i.e., AccLow-DecLow; AccLow-DecHigh; AccHigh-DecLow; AccHigh-DecHigh). The participants' perception of body rotation was assessed by computing the gain, i.e., ratio between the amplitude of the perceived rotations (as measured by the rotating manipulandum's handle) and the amplitude of the actual chair rotations. The gain was measured at the end of the rotations, and was also computed separately for the acceleration and deceleration phases. Three salient findings resulted from this experiment: (i) the gain was much greater during body acceleration than during body deceleration, (ii) the gain was greater during High compared to Low accelerations and (iii) the gain measured during the deceleration was influenced by the preceding acceleration (i.e., Low or High). These different effects of the angular stimuli on the perception of body motion can be interpreted in relation to the consequences of body acceleration and deceleration on the vestibular system and on higher-order cognitive processes.


Brain-immune crosstalk in the treatment of major depressive disorder.
A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation.


Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells.
In this report, we demonstrate for autoreactive T cell clones that single amino acid modifications of the antigenic ligand can result in not only abrogated, decreased, or unmodified, but also increased, T cell responsiveness (superagonist ligands). We further studied the effects of combinations of multiple substitutions with different effects in single peptides. Experiments with peptides carrying multiple amino acid exchanges revealed that the final outcome of TCR ligation by a given ligand is the integration of negative, neutral, and positive effects of each single residue. In addition, the introduction of superagonist substitutions together with nonconservative modifications of primary and secondary TCR contacts resulted in stimulatory ligands. These findings indicate that: 1) the specificity of a single TCR is highly degenerate; 2) ligands exist for autoreactive T cells that have higher agonist activity than the autoantigen itself; 3) the rules to search for cross-reactive epitopes in autoimmunity should take into account that amino acids at certain positions within an antigenic peptide may exert superagonist activity and compensate for the negative effects of residues at other positions that would otherwise not be tolerated.


Food plating preferences of children: the importance of presentation on desire for diversity.
Given the importance of food presentation and childhood nutrition, we aimed to test the degree to which adults and children might demonstrate different preferences for various ways in which food can be presented on plates. Twenty-three pre-teen children and 46 adults were individually presented full-size photos of 48 different combinations of food on plates. The photos varied according to seven dimensions (e.g. number of items, placement of entrée and organization of the food). Contrary to the default assumption that parents and children share preferences for the ways in which food is presented on plates, we find that children have notably different preferences than adults. Most remarkably, we show that children tended to prefer seven different items and six different colours on their ideal plates, while adults tended to prefer three different colours and three different items. The assumption that children prefer food presentations that match adult preferences appears to be unjustified. Future research and interventions that are designed to improve childhood nutrition should test for the impact of diverse presentations on actual food consumption among a variety of populations across institutional settings.


Exercise during pregnancy: the role of obstetric providers.
Obstetric providers are logical choices for conveying information about physical activity to their pregnant patients. However, research regarding obstetric providers counseling pregnant patients about physical activity is sparse. To investigate the association between obstetric providers discussing exercise with their pregnant patients and patients' exercise behaviors and to explore factors related to obstetric providers discussing exercise and other health behaviors (tobacco use, alcohol use, and nutrition) with their patients. We received completed surveys from 238 pregnant women and 31 obstetric providers at 12 obstetrician offices. The offices were located throughout the United States and were heterogeneous in regards to patient insurance coverage, number of patients treated per month, and percentage of patients with complications. Women who were "more careful about eating healthy" (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.2-8.0) and who discussed exercise with their obstetric provider (OR, 2.2; 95% CI, 1.1-4.3) were more likely to "maintain or increase exercise" during pregnancy than those who were not conscientious about their diets and those who did not discuss exercise with their obstetric provider, respectively. The odds of obstetric providers discussing exercise with pregnant patients increased 7-fold (OR, 7.1; 95% CI, 1.4-37.3) for each health behavior the obstetric provider discussed with the patient. Patient discussions with obstetric providers about exercise and patient attention to eating habits are associated with exercising during pregnancy. A more multibehavioral approach by obstetric providers may improve the likelihood that patients exercise during pregnancy.


Synaptic Plasticity in Cardiac Innervation and Its Potential Role in Atrial Fibrillation.
Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the neurons innervating the heart. The atria receive rich innervation from the autonomic branch of the peripheral nervous system. Sympathetic neurons are clustered in stellate and cervical ganglia alongside the spinal cord and extend fibers to the heart directly innervating the myocardium. These neurons are major drivers of hyperactive sympathetic activity observed in heart disease, ventricular arrhythmias, and sudden cardiac death. Both pre- and postsynaptic changes have been observed to occur at synapses formed by sympathetic ganglion neurons, suggesting that plasticity at sympathetic neuro-cardiac synapses is a major contributor to arrhythmias. Less is known about the plasticity in parasympathetic neurons located in clusters on the heart surface. These neuronal clusters, termed ganglionated plexi, or "little brains," can independently modulate neural control of the heart and stimulation that enhances their excitability can induce arrhythmia such as atrial fibrillation. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by ganglionated plexi neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation.


ANK1 is up-regulated in laser captured microglia in Alzheimer's brain; the importance of addressing cellular heterogeneity.
Recent epigenetic association studies have identified a new gene, ANK1, in the pathogenesis of Alzheimer's disease (AD). Although strong associations were observed, brain homogenates were used to generate the data, introducing complications because of the range of cell types analyzed. In order to address the issue of cellular heterogeneity in homogenate samples we isolated microglial, astrocytes and neurons by laser capture microdissection from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis of AD and matched control cases. Using this unique RNAseq data set, we show that in the hippocampus, ANK1 is significantly (p<0.0001) up-regulated 4-fold in AD microglia, but not in neurons or astrocytes from the same individuals. These data provide evidence that microglia are the source of ANK1 differential expression previously identified in homogenate samples in AD.


Impact of prenatal cocaine exposure on child behavior problems through school age.
We examined the trajectory of childhood behavior problems after prenatal cocaine exposure. The Maternal Lifestyle Study, a longitudinal cohort study, enrolled children between 1993 and 1995 at 4 centers. Prenatal cocaine exposure was determined from mothers who admitted use and/or meconium results. Exposed children were matched with a group of nonexposed children within site and by gestational age, gender, race, and ethnicity. The study began at the 1-month corrected age with a total of 1388 children enrolled. A total of 1056 were assessed for internalizing, externalizing, and total behavior problems at ages 3, 5, and 7 years using the Child Behavior Checklist. Longitudinal hierarchical linear models were used to determine the effect of prenatal cocaine exposure on behavior problem trajectories while controlling for other prenatal exposures; time-varying covariates, including ongoing caregiver use of legal and illegal substances; demographic factors; family violence; and caregiver psychological distress. High prenatal cocaine exposure was associated with the trajectory of internalizing, externalizing, and total behavior problems; these effects were independent of and less than the significant combined effect of prenatal and postnatal tobacco and alcohol exposures. Caregiver depression and family violence had independent negative influence on all behavior outcomes. Prenatal cocaine exposure has a negative impact on the trajectories of childhood behavior outcomes. When they co-occur with prenatal cocaine exposure, prenatal and postnatal tobacco and alcohol exposures have added negative effects on behavior outcomes.


A Delphi study to establish consensus on a definition of major bleeding in adult trauma.
The majority of potentially preventable deaths in trauma are due to uncontrolled hemorrhage and occur early after injury. How major bleeding is defined is integral to early identification and treatment of this group of high-risk patients. However, there is no consensus on a definition of major bleeding in trauma. The aim of this Delphi study was to develop a consensus definition for research, with transfusion used as a surrogate marker of bleeding. Trauma experts from three international groups were invited to take part in an online Delphi survey. Over the course of four rounds, the group developed a number of definitions of major bleeding and reached consensus on a new definition. Forty-four trauma experts agreed to become members of the Delphi panel, and 30 of 44 (68%) completed all four rounds. The panel agreed to exclude the historical massive transfusion definition (≥10 units of red blood cells within 24 hours). Consensus was reached on a new definition for use in clinical research: 4 or more units of any blood component within 2 hours of injury. This Delphi process has yielded a pragmatic transfusion-based definition of major bleeding. The consensus definition differs from historical definitions: a shorter time frame to reflect the acuity of bleeding, and multiple blood components in keeping with a balanced approach to resuscitation. The definition developed may be best suited to mature trauma systems (reflecting the demographics of the expert panel), and could be used to guide registry data recording and to characterize patients at risk of major bleeding.


Targeting RNA with small molecules: from fundamental principles towards the clinic.
Recent advances in our understanding of RNA biology have uncovered crucial roles for RNA in multiple disease states, ranging from viral and bacterial infections to cancer and neurological disorders. As a result, multiple laboratories have become interested in developing drug-like small molecules to target RNA. However, this development comes with multiple unique challenges. For example, RNA is inherently dynamic and has limited chemical diversity. In addition, promiscuous RNA-binding ligands are often identified during screening campaigns. This Tutorial Review overviews important considerations and advancements for generating RNA-targeted small molecules, ranging from fundamental chemistry to promising small molecule examples with demonstrated clinical efficacy. Specifically, we begin by exploring RNA functional classes, structural hierarchy, and dynamics. We then discuss fundamental RNA recognition principles along with methods for small molecule screening and RNA structure determination. Finally, we review unique challenges and emerging solutions from both the RNA and small molecule perspectives for generating RNA-targeted ligands before highlighting a selection of the "Greatest Hits" to date. These molecules target RNA in a variety of diseases, including cancer, neurodegeneration, and viral infection, in cellular and animal model systems. Additionally, we explore the recently FDA-approved small molecule regulator of RNA splicing, risdiplam, for treatment of spinal muscular atrophy. Together, this Tutorial Review showcases the fundamental role of chemical and molecular recognition principles in enhancing our understanding of RNA biology and contributing to the rapidly growing number of RNA-targeted probes and therapeutics. In particular, we hope this widely accessible review will serve as inspiration for aspiring small molecule and/or RNA researchers.


Recurrent cerebral arteriovenous malformations after negative postoperative angiograms.
Angiography has been considered to be the gold standard to judge the success of treatment for cerebral arteriovenous malformations (AVMs). Patients without residual nidus or early draining veins on postoperative angiograms are considered cured, with the risk of hemorrhage eliminated. A series of five patients with recurrent AVMs after negative postoperative angiography is described. All patients had hemispheric AVMs, presented initially with hemorrhage, and were between 5 and 13 years of age. Recurrence was noted 1 to 9 years later (at 12-16 years of age); after a hemorrhage in three patients, seizures in one, and on follow-up magnetic resonance imaging in one. Four patients underwent angiography that showed recurrence of the AVM at or adjacent to the original site. Three years postsurgery, the fifth patient died from a large intracerebral and intraventricular hemorrhage originating in the previous location of the AVM; however, the patient did not undergo angiography at the time of recurrence. The initial negative angiograms obtained postoperatively in these patients may be explained by postoperative spasm or thrombosis of a small residual malformation. However, in the authors' cumulative experience with 808 patients who have undergone complete surgical removal of AVMs (of whom 667 were older than 18 years of age), no case of recurrent AVM has been observed in an adult. Therefore, actual regrowth of an AVM may occur in children and could be a consequence of their relatively immature cerebral vasculature and may involve active angiogenesis mediated by humoral factors. The present findings argue against the assumption that AVMs are strictly congenital lesions resulting from failure of capillary formation during early embryogenesis. It is concluded that delayed imaging studies should be considered in children at least 1 year after their initial negative postoperative arteriogram to exclude a recurrent AVM.


[Phlebopathies: aetiology and therapeutic management].
Phlebopathy is an ambiguously interpreted term. In the Russian literature, it implies functional disorders of the venous system, albeit not seriously jeopardizing, however substantially decreasing quality of life. Phlebopathies may be induced by different causes, not infrequently common with the risk factors of chronic venous insufficiency. The present work deals with the classification, pathogenesis and epidemiology of phlebopathies, as well as the results of the original studies on management of hormone-induces phlebopathy. Hormone-induced phlebopathy - symptoms of phlebopathy or chronic venous insufficiency induced by long-term intake of combined oral contraceptives (COCs). To optimize treatment of the pathology concerned, we examined three groups of female patients (112 women) suffering from hormone-induced phlebopathy of the lower limbs. In Group One patients, COCs were discontinued with no administration of venotonic agents. Group Two patients along with withdrawal of COCs were given Antistax, as well as elastic compression. Group Three patients continued receiving COCs accompanied by simultaneous treatment with Antistax. During the study, we determined the malleolar volume, also assessing the degree of subjective symptoms, and quality of life. It was shown that withdrawal of COCs alone was not sufficient to stop symptoms of phlebopathy. Antistax efficiently stops the majority of these clinical manifestations, even on the background of intake of contraceptives. The maximal effect was observed in discontinuation of the COCs, intake of Antistax and prescription of elastic compression.


Case Study: Extreme Weight Making Causes Relative Energy Deficiency, Dehydration, and Acute Kidney Injury in a Male Mixed Martial Arts Athlete.
The aim of the present case study was to quantify the physiological and metabolic impact of extreme weight cutting by an elite male mixed martial arts athlete. Throughout an 8-week period, we obtained regular assessments of body composition, resting metabolic rate, peak oxygen uptake, and blood clinical chemistry to assess endocrine status, lipid profiles, hydration, and kidney function. The athlete adhered to a "phased" weight loss plan consisting of 7 weeks of reduced energy (ranging from 1,300 to 1,900 kcal/day) intake (Phase 1), 5 days of water loading with 8 L/day for 4 days followed by 250 ml on Day 5 (Phase 2), 20 hr of fasting and dehydration (Phase 3), and 32 hr of rehydration and refueling prior to competition (Phase 4). Body mass declined by 18.1% (80.2 to 65.7 kg) corresponding to changes of 4.4, 2.8, and 7.3 kg in Phases 1, 2, and 3, respectively. We observed clear indices of relative energy deficiency, as evidenced by reduced resting metabolic rate (-331 kcal), inability to complete performance tests, alterations to endocrine hormones (testosterone: <3 nmol/L), and hypercholesterolemia (>6 mmol/L). Moreover, severe dehydration (reducing body mass by 9.3%) in the final 24 hr prior to weigh-in-induced hypernatremia (plasma sodium: 148 mmol/L) and acute kidney injury (serum creatinine: 177 μmol/L). These data, therefore, support publicized reports of the harmful (and potentially fatal) effects of extreme weight cutting in mixed martial arts athletes and represent a call for action to governing bodies to safeguard the welfare of mixed martial arts athletes.


Rapid analysis of Listeria monocytogenes cell wall teichoic acid carbohydrates by ESI-MS/MS.
We report the application of electrospray ionization (ESI) mass spectrometry for compositional characterization of wall teichoic acids (WTA), a major component of gram-positive bacterial cell walls. Tandem mass spectrometry (ESI-MS/MS) of purified and chemically hydrolyzed monomeric WTA components provided sufficient information to identify WTA monomers and their specific carbohydrate constituents. A lithium matrix was used for ionization of uncharged WTA monomers, and successfully applied to analyze the WTA molecules of four Listeria strains differing in carbohydrate substitution on a conserved polyribitol-phosphate backbone structure. Carbohydrate residues such as N-acetylglucosamine or rhamnose linked to the WTA could directly be identified by ESI-MS/MS, circumventing the need for quantitative analysis by gas chromatography. The presence of a terminal N-acetylglucosamine residue tethered to the ribitol was confirmed using fluorescently labeled wheat-germ agglutinin. In conclusion, the mass spectrometry method described here will greatly facilitate compositional analysis and characterization of teichoic acids and similar macromolecules from diverse bacterial species, and represents a significant advance in the identification of serovar-specific carbohydrates and sugar molecules on bacteria.


Mortality after lower extremity fractures in men with spinal cord injury.
In the United States, there are over 200,000 men with spinal cord injuries (SCIs) who are at risk for lower limb fractures. The risk of mortality after fractures in SCI is unknown. This was a population-based, cohort study of all male veterans (mean age 54.1; range, 20.3-100.5 years) with a traumatic SCI of at least 2 years' duration enrolled in the Veterans Affairs (VA) Spinal Cord Dysfunction Registry from FY2002 to FY2010 to determine the association between lower extremity fractures and mortality. Mortality for up to 5 years was determined. The lower extremity fracture rate was 2.14 per 100 patient-years at risk for at least one fracture. In unadjusted models and in models adjusted for demographic, SCI-related factors, healthcare use, and comorbidities, there was a significant association between incident lower extremity fracture and increased mortality (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17-1.63; HR, 1.36; 95% CI, 1.15-1.61, respectively). In complete SCI, the hazard of death after lower extremity fracture was also increased (unadjusted model: HR, 1.46; 95% CI, 1.13-1.89; adjusted model: HR, 1.32; 95% CI, 1.02-1.71). In fully-adjusted models, the association of incident lower extremity fracture with increased mortality was substantially greater in older men (age ≥50 years) for the entire cohort (HR, 3.42; 95% CI, 2.75-4.25) and for those with complete SCI (HR, 3.13; 95% CI, 2.19-4.45), compared to younger men (age <50 years) (entire cohort: HR, 1.42; 95% CI, 0.94-2.14; complete SCI: HR, 1.71; 95% CI, 0.98-3.01). Every additional point in the Charlson comorbidity index was associated with a 10% increase in the hazard of death in models involving the entire cohort (HR, 1.11; 95% CI, 1.09-1.13) and also in models limited to men with complete SCI (HR, 1.10; 95% CI, 1.06-1.15). These data support the concept that both the fracture itself and underlying comorbidities are drivers of death in men with SCI.


The relation between leadership style and empowerment on job satisfaction of nurses.
The authors explore the relation between leadership style and empowerment and its effect on job satisfaction among the nursing staff of a regional medical center. Several empirical studies on transformational leadership-found that transformational leadership behaviors were positively related to work team success and leadership effectiveness. Transformational leadership processes have also been suggested to enhance followers' work-oriented values and shape the self-efficacies of followers. Employee empowerment may be influenced by the perception that the organization cares about its employees' well-being and that their work is valued. Empowering nurses may increase job satisfaction and improve patient care. Leadership style and empowerment influence job satisfaction among workers. All nursing department staff were invited to complete a self-report questionnaire with no identifying information. Leadership style was measured using Bass's Multifactor Leadership Questionnaire, empowerment was measured with items from Spreitzer's Psychological Empowerment instrument, and job satisfaction was measured by Warr, Cook, and Wall's job satisfaction questionnaire. Both transformational and transactional leadership were positively related to job satisfaction, as was empowerment. Differences in the contributions of empowerment and leadership style in predicting job satisfaction for licensed and unlicensed workers was evident. Designing interventions that allow for the relative influence of leadership style as well as empowerment on varying classifications of nursing personnel may be a more effective strategy and have a greater effect on staff attitudes and behaviors.


Characterization of the lipid envelope of exosome encapsulated HEV particles protected from the immune response.
The hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide. Although HEV is a small, naked RNA virus, HEV particles become associated with lipids in the blood of infected patients and in the supernatant of culture systems. The egress of these particles from cells implies the exocytosis pathway but the question of the role of the resulting HEV RNA containing exosomes and the nature of the lipids they contain has not been fully addressed. We determined the lipid proportions of exosomes from uninfected and HEV-infected cells and their role in HEV spreading. We cultured a suitable HEV strain on HepG2/C3A cells and analyzed the population of exosomes containing HEV RNA using lipidomics methods and electron microscopy. We also quantified HEV infectivity using an infectivity endpoint method based on HEV RNA quantification to calculate the tissue culture infectious dose 50. Exosomes produced by HEV-infected HepG2/C3A cells contained encapsidated HEV RNA. These HEV RNA-containing exosomes were infectious but ten times less than stools. HEV from stools, but not exosome-associated HEV from culture supernatant, was neutralized by anti-HEV antibodies in a dose-dependent manner. HEV infection did not influence the morphology or lipid proportions of the bulk of exosomes. These exosomes contained significantly more cholesterol, phosphatidylserine, sphingomyelin and ceramides than the parent cells, but less phosphoinositides and polyunsaturated fatty acids. Exosomes play a major role in HEV egress but HEV infection does not modify the characteristics of the bulk of exosomes produced by infected cells. PS and cholesterol enriched in these vesicles could then be critical for HEV entry. HEV particles in exosomes are protected from the immune response which could lead to the wide circulation of HEV in its host.


Précis of The rational imagination: how people create alternatives to reality.
The human imagination remains one of the last uncharted terrains of the mind. People often imagine how events might have turned out "if only" something had been different. The "fault lines" of reality, those aspects more readily changed, indicate that counterfactual thoughts are guided by the same principles as rational thoughts. In the past, rationality and imagination have been viewed as opposites. But research has shown that rational thought is more imaginative than cognitive scientists had supposed. In The Rational Imagination, I argue that imaginative thought is more rational than scientists have imagined. People exhibit remarkable similarities in the sorts of things they change in their mental representation of reality when they imagine how the facts could have turned out differently. For example, they tend to imagine alternatives to actions rather than inactions, events within their control rather than those beyond their control, and socially unacceptable events rather than acceptable ones. Their thoughts about how an event might have turned out differently lead them to judge that a strong causal relation exists between an antecedent event and the outcome, and their thoughts about how an event might have turned out the same lead them to judge that a weaker causal relation exists. In a simple temporal sequence, people tend to imagine alternatives to the most recent event. The central claim in the book is that counterfactual thoughts are organised along the same principles as rational thought. The idea that the counterfactual imagination is rational depends on three steps: (1) humans are capable of rational thought; (2) they make inferences by thinking about possibilities; and (3) their counterfactual thoughts rely on thinking about possibilities, just as rational thoughts do. The sorts of possibilities that people envisage explain the mutability of certain aspects of mental representations and the immutability of other aspects.


Microalgal mediation of ripple mobility.
The interaction between physical and biological factors responsible for the cessation of ripple migration on a sandy intertidal flat was examined during a microalgal bloom period in late winter/early spring, as part of a wider study into the biostabilisation of intertidal sediments. Ripple positions and ripple geometry were monitored, and surface sediment was sampled, at weekly intervals over a 5-week period. Ripples remained in the same position for at least 4 weeks, during which time there was a progressive reduction in bedform height (smoothing) and deposition of some 1.5 cm sediment, mainly in the ripple troughs (surface levelling). The mean chlorophyll a (chl a) sediment content was 6.0 microg gDW(-1) (DW: dry weight) (0-1 mm depth fraction), with a maximum value of 7.4 microg gDW(-1) half way through the bloom. Mean colloidal-S carbohydrate (S: saline extraction) content was 131 microg GE gDW(-1) (GE: glucose equivalent) (0-1 mm), with a maximum of 261 microg GE gDW(-1 )towards the end of the bloom. Important accessory pigments were peridinin (indicative of dinophytes) and fucoxanthin (diatoms). Stepwise multiple regression showed that peridinin was the best predictor of chl a. For the first time, in situ evidence for the mediation of (wave) ripple migration by microalgae is provided. Results indicate that diatoms, and quite possibly dinophytes, can have a significant effect on intertidal flat ripple mobility on a temporal scale of weeks. In addition, microalgal effects appear capable of effecting a reduction in bed roughness on a spatial scale of up to 10(-2 )m, with a subsequent reduction in bottom stress and bed erodability. It is suggested that a unique combination of environmental conditions, in conjunction with the microalgal bloom(s), promoted the initial cessation of ripple movement, and that stationary-phase, diatom-derived extracellular polymeric substances (EPS) (and possibly dinophyte-derived EPS) may have prolonged the condition. It is reasonable to suppose that ripple stabilisation by similar processes may have contributed to ripple mark preservation in the geological record. A conceptual model of sandy intertidal flat processes is presented, illustrating two conditions: (i) a low EPS/microalgae sediment content with low ripple stabilisation and preservation potential; and (ii) a high EPS/microalgae content with higher preservation potential.


β Cell Replacement Therapy: The Next 10 Years.
β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.


Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5.
Mitogen-activated protein (MAP) kinases are essential regulators in immune responses, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved. A number of mammalian MKPs have been identified so far, but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 (also known as Dusp10)-deficient mouse cells. Mkp5-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4(+) and CD8(+) effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.


Targeting children of substance-using parents with the community-based group intervention TRAMPOLINE: a randomised controlled trial--design, evaluation, recruitment issues.
Children of substance-abusing parents are at risk for developing psychosocial development problems. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated programme for children from substance-affected families exists in Germany. The study described in this protocol is designed to test the effectiveness of the group programme TRAMPOLINE for children aged 8-12 years with at least one substance-abusing or -dependent caregiver. The intervention is specifically geared to issues and needs of children from substance-affected families. The effectiveness of the manualised nine-session group programme TRAMPOLINE is tested among N = 218 children from substance-affected families in a multicentre randomised controlled trial. Outpatient counselling facilities across the nation from different settings (rural/urban, Northern/Southern/Eastern/Western regions of the country) will deliver the interventions, as they hold the primary access to the target group in Germany. The control condition is a group programme with the same duration that is not addiction-specific. We expect that participants in the intervention condition will show a significant improvement in the use of adaptive coping strategies (in general and within the family) compared to the control condition as a direct result of the intervention. Data is collected shortly before and after as well as six months after the intervention. In Germany, the study presented here is the first to develop and evaluate a programme for children of substance-abusing parents. Limitations and strengths are discussed with a special focus on recruitment challenges as they appear to be the most potent threat to feasibility in the difficult-to-access target group at hand (Trial registration: ISRCTN81470784).


EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat.
Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.


Effects of a School-Based Sports Program on Physical Fitness, Physical Activity, and Cardiometabolic Health in Youth With Physical Disabilities: Data From the Sport-2-Stay-Fit Study.
To investigate the effects of a school-based once-a-week sports program on physical fitness, physical activity, and cardiometabolic health in children and adolescents with a physical disability. This controlled clinical trial included 71 children and adolescents from four schools for special education [mean age 13.7 (2.9) years, range 8-19, 55% boys]. Participants had various chronic health conditions including cerebral palsy (37%), other neuromuscular (44%), metabolic (8%), musculoskeletal (7%), and cardiovascular (4%) disorders. Before recruitment and based on the presence of school-based sports, schools were assigned as sport or control group. School-based sports were initiated and provided by motivated experienced physical educators. The sport group (n = 31) participated in a once-a-week school-based sports program for 6 months, which included team sports. The control group (n = 40) followed the regular curriculum. Anaerobic performance was assessed by the Muscle Power Sprint Test. Secondary outcome measures included aerobic performance, VO2 peak, strength, physical activity, blood pressure, arterial stiffness, body composition, and the metabolic profile. A significant improvement of 16% in favor of the sport group was found for anaerobic performance (p = 0.003). In addition, the sport group lost 2.8% more fat mass compared to the control group (p = 0.007). No changes were found for aerobic performance, VO2 peak, physical activity, blood pressure, arterial stiffness, and the metabolic profile. Anaerobic performance and fat mass improved following a school-based sports program. These effects are promising for long-term fitness and health promotion, because sports sessions at school eliminate certain barriers for sports participation and adding a once-a-week sports session showed already positive effects for 6 months. This trial was registered with the Dutch Trial Registry (NTR4698).


Age-related differences when walking downhill on different sloped terrains.
Despite the common situation of walking on different sloped terrains, previous work on gait has focused on level terrain. This study aims to assess whether any age-related differences exist in spatiotemporal and stability parameters when walking downhill on three different sloped walkways. Two tri-axial accelerometers were used at the levels of head and pelvis to investigate spatiotemporal parameters, magnitude (root mean square, RMS), harmonic content of accelerations (harmonic ratios, HR) and attenuation between body levels (ATT) in 35 older adults (OA, 69 ± 4.5 y.o.) and 22 young adults (YA, 22.1 ± 1.9 y.o.). Older adults walked at the same speed and cadence as young adults in flat terrain (FL, 0%) and moderate hill (MH, 8%). In the highest slope (PH, 20%), older adults reduced speed and step length and both groups increased cadence. Age had no effect on attenuation and RMS profiles. RMS increased with slope in all directions at both head and pelvis, except, for medio-lateral direction (ML), with similar head RMS in all slopes. There is an important shift in ATT from anteroposterior direction (AP) to ML at the highest slope, resulting in smaller antero-posterior attenuation and greater medio-lateral attenuation. Age differences appeared in the smoothness (HR) at the flat terrain, with increased vertical and antero-posterior values for young adults. As slope increased, group differences disappeared and HR decreased for all directions of motion. In general, spatiotemporal adaptations to increased slope seem to be part of a mechanism to improve ML attenuation, in both young and old adults.


Two single-nucleotide polymorphisms in the 5' and 3' ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus.
To test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE). The coding 5' and 3' flanking regions of the OPN gene were scanned for polymorphisms by denaturing high-performance liquid chromatography. A case-control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme-linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes. Among the 13 detected single-nucleotide polymorphisms (SNPs), alleles -156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [P(corr)] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, P(corr) = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38-4.02) for SNP -156 and an OR of 1.57 (95% CI 1.16-2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8-fold higher (95% CI 2.0-7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and -156 genotypes (overall P = 0.0011, P(corr) = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels. These data suggest the independent effect of a promoter (-156) and a 3'-untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.


Interferon-γ release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis.
Despite the widespread use of interferon-γ release assays (IGRAs), their role in diagnosing tuberculosis and targeting preventive therapy in HIV-infected patients remains unclear. We conducted a comprehensive systematic review to contribute to the evidence-based practice in HIV-infected people. We searched MEDLINE, Cochrane, and Biomedicine databases to identify articles published between January 2005 and July 2011 that assessed QuantiFERON®-TB Gold In-Tube (QFT-GIT) and T-SPOT®.TB (T-SPOT.TB) in HIV-infected adults. We assessed their accuracy for the diagnosis of tuberculosis and incident active tuberculosis, and the proportion of indeterminate results. The search identified 38 evaluable studies covering a total of 6514 HIV-infected participants. The pooled sensitivity and specificity for tuberculosis were 61% and 72% for QFT-GIT, and 65% and 70% for T-SPOT.TB. The cumulative incidence of subsequent active tuberculosis was 8.3% for QFT-GIT and 10% for T-SPOT.TB in patients tested positive (one study each), and 0% for QFT-GIT (two studies) and T-SPOT.TB (one study) respectively in those tested negative. Pooled indeterminate rates were 8.2% for QFT-GIT and 5.9% for T-SPOT.TB. Rates were higher in high burden settings (12.0% for QFT-GIT and 7.7% for T-SPOT.TB) than in low-intermediate burden settings (3.9% for QFT-GIT and 4.3% for T-SPOT.TB). They were also higher in patients with CD4(+) T-cell count <200 (11.6% for QFT-GIT and 11.4% for T-SPOT.TB) than in those with CD4(+) T-cell count ≥ 200 (3.1% for QFT-GIT and 7.9% for T-SPOT.TB). IGRAs have suboptimal accuracy for confirming or ruling out active tuberculosis disease in HIV-infected adults. While their predictive value for incident active tuberculosis is modest, a negative QFT-GIT implies a very low short- to medium-term risk. Identifying the factors associated with indeterminate results will help to optimize the use of IGRAs in clinical practice, particularly in resource-limited countries with a high prevalence of HIV-coinfection.


Repetitive Dosing of Fumed Silica Leads to Profibrogenic Effects through Unique Structure-Activity Relationships and Biopersistence in the Lung.
Contrary to the notion that the use of fumed silica in consumer products can "generally (be) regarded as safe" (GRAS), the high surface reactivity of pyrogenic silica differs from other forms of synthetic amorphous silica (SAS), including the capacity to induce membrane damage and acute proinflammatory changes in the murine lung. In addition, the chain-like structure and reactive surface silanols also allow fumed silica to activate the NLRP3 inflammasome, leading to IL-1β production. This pathway is known to be associated with subchronic inflammation and profibrogenic effects in the lung by α-quartz and carbon nanotubes. However, different from the latter materials, bolus dose instillation of 21 mg/kg fumed silica did not induce sustained IL-1β production or subchronic pulmonary effects. In contrast, the NLRP3 inflammasome pathway was continuously activated by repetitive-dose administration of 3 × 7 mg/kg fumed silica, 1 week apart. We also found that while single-dose exposure failed to induce profibrotic effects in the lung, repetitive dosing can trigger increased collagen production, even at 3 × 3 mg/kg. The change between bolus and repetitive dosing was due to a change in lung clearance, with recurrent dosing leading to fumed silica biopersistence, sustained macrophage recruitment, and activation of the NLRP3 pathway. These subchronic proinflammatory effects disappeared when less surface-reactive titanium-doped fumed silica was used for recurrent administration. All considered, these data indicate that while fumed silica may be regarded as safe for some applications, we should reconsider the GRAS label during repetitive or chronic inhalation exposure conditions.


Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for Endometriosis: A Randomized Controlled Trial.
To assess whether add-back therapy with norethindrone acetate or norethindrone acetate plus conjugated equine estrogens is superior to maintain bone health in adolescents and young women using gonadotropin-releasing hormone agonists for endometriosis. Gonadotropin-releasing hormone agonists are associated with deleterious effects on bone. Hormonal add-back may mitigate these effects. Adolescents and young women (n=51) received a random, double-blind assignment to add-back with norethindrone acetate (5 mg/day) plus conjugated equine estrogens (0.625 mg/day) or norethindrone acetate plus placebo for 12 months. Body composition, bone mineral content, and bone mineral density (BMD) were obtained by dual-energy X-ray absorptiometry every 6 months. Quality-of-life measures were collected every 3 months. Intention-to-treat comparison of outcomes was conducted by repeated-measures analysis of variance. Thirty-four adolescents and young women completed the trial; dropouts did not differ from those who completed the trial. Bone mineral density was normal at baseline. At 12 months, total body bone mineral content and BMD had increased in the norethindrone acetate plus conjugated equine estrogens group (bone mineral content +37 g, P<.001 and BMD +0.012 g/cm, P=.05), but not in those receiving norethindrone acetate plus placebo (bone mineral content P=.19 and BMD P=.95). Lean mass increased only in those receiving conjugated equine estrogens (+1.4 kg, P=.001). Improvements in physical functioning domains of quality-of-life assessments were greater with norethindrone acetate plus conjugated equine estrogens (P=.005). No differences were seen at the hip or lumbar spine by dual-energy X-ray absorptiometry. No significant adverse events occurred. Hormonal add-back successfully preserved bone health and improved quality of life for adolescents and young women with endometriosis during 12 months of gonadotropin-releasing hormone agonist therapy. Combination norethindrone acetate plus conjugated equine estrogens add-back appears to be more effective for increasing total body bone mineral content, areal BMD, and lean mass than norethindrone acetate monotherapy. ClinicalTrials.gov; www.clinicaltrials.gov, NCT00474851. I.


Mesenchymal stem cells and neuroregeneration in Parkinson's disease.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by a progressive and extensive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and their terminals in the striatum, which results in debilitating movement disorders. This devastating disease affects over 1 million individuals in the United States and is increasing in incidence worldwide. Currently available pharmacological and surgical therapies ameliorate clinical symptoms in the early stages of disease, but they cannot stop or reverse degeneration of DA neurons. Stem cell therapies have come to the forefront of the PD research field as promising regenerative therapies. The majority of preclinical stem cell studies in experimental models of PD are focused on the idea that stem cell-derived DA neurons could be developed for replacement of diseased neurons. Alternatively, our studies and the studies from other groups suggest that stem cells also have the potential to protect and stimulate regeneration of compromised DA neurons. This review is focused on strategies based on the therapeutic potential for PD of the neurotrophic and neuroregenerative properties of a subclass of stem cells, mesenchymal stem cells (MSCs).


Evaluation of the updated Vitek yeast identification data base.
Using 398 isolates of yeasts and yeastlike fungi comprising 9 genera and 26 species, as well as the hyphomycete Geotrichum candidum and the achlorophyllous alga Prototheca wickerhamii, we compared the API 20C yeast identification system with the modified Vitek yeast identification system with an expanded data base. We found 11 discrepancies between the two systems: five (1.3%) of the isolates (Blastoschizomyces capitatus, 1; Candida albicans, 1; Hansenula anomala, 1; Rhodotorula minuta, 2) had biocodes not included in the expanded Vitek data base, and six (1.5%) of the isolates (Candida lusitaniae, 1; Candida parapsilosis, 1; Cryptococcus uniguttulatus, 1; H. anomala, 1; Torulopsis candida, 2) were misidentified by the Vitek system. Overall, the efficacy of the Vitek system compares favorably with that of the API 20C in the identification of clinically important yeasts.


A Specific Melon Concentrate Exhibits Photoprotective Effects from Antioxidant Activity in Healthy Adults.
Skin is the largest body organ and the first barrier to exogenous threats. This organ is constantly exposed to external factors such as ultraviolet radiation, which induces many adverse effects including sunburn, depigmentation, photo aging, photo immune suppression, and even skin cancer. Antioxidants seem to be good candidates in order to reduce ultraviolet-mediated damages and to prevent the health consequences of ultraviolet exposure. The present investigation aims to further characterize the potential skin photoprotective effects of a food supplementation and a topical administration of a melon concentrate alone or in combination. A clinical study assessing the Minimal Erythema Dose (MED) was first set up to evaluate photoprotection. Afterward, an independent in vitro study was performed on human skin explants from a donor to evaluate the effect of the melon concentrate at different levels including on the sunburn cells formation and on the endogenous antioxidant enzymes and its influence on melanin. Clinical study results demonstrate that melon concentrate application and/or supplementation increased MED. It also increased the endogenous antioxidant enzymes and reduced sunburn cells and melanin level on irradiated skin explants. Therefore, it is suggested that melon concentrate administration (oral and/or topical) could be a useful strategy for photoprotection due to its antioxidant properties.


Vancomycin use in 2 Ontario tertiary care hospitals: a survey.
Use of vancomycin is a risk factor for acquiring vancomycin-resistant enterococci (VRE). To optimize the use of vancomycin in hospitals, the Hospital Infection Control Practices Advisory Committee (HICPAC) published recommendations in 1995. The objectives of this study were to determine the frequency, indications, and risk factors for inappropriate inpatient vancomycin prescriptions before and after publication of the HICPAC recommendations. Cross-sectional study. Two tertiary care hospitals in Ontario. Vancomycin prescriptions were randomly sampled and hospital chart view performed for two 12-month periods, one before and one after publication of the HICPAC recommendations on vancomycin use. Based on the review of 189 charts from hospital A and 190 from hospital B, there was no significant change in the proportion of inappropriate vancomycin prescriptions at either hospital from before publication of the HICPAC recommendations to afterward (63% v. 71% at hospital A, p = 0.21; 48% v. 37% at hospital B, p = 0.11). In 51% of all vancomycin prescriptions, the drug was prescribed instead of another antibiotic because of a recorded penicillin allergy. Surgical prophylaxis with more than 1 or 2 doses of vancomycin accounted for 66% (hospital A) and 58% (hospital B) of inappropriate prescriptions. In a multivariate analysis, surgical prophylaxis remained a significant risk factor for inappropriate use of vancomycin at both hospitals (odds ratio [OR] 5.6, 95% confidence interval [CI] 2.8 to 11.3, p = 0.01 for hospital A; OR 13.9, 95% CI 4.9 to 39.5, p = 0.01 for hospital B). Prescription by the orthopedic service also remained a significant risk factor in the final logistic regression model for hospital B (OR 3.9, 95% CI 1.1 to 13.9, p = 0.01). A high proportion of vancomycin prescriptions, surveyed before and after publication of the HICPAC recommendations on vancomycin use, were inappropriate. Excessive vancomycin use in surgical prophylaxis was an important factor. Our findings suggest that the use of standardized peri-operative order forms and of penicillin-allergy testing may help optimize vancomycin use in tertiary care hospitals.


A technique for calculating the amplitude distribution of propagated fields by Gaussian sampling.
We present a technique to solve numerically the Fresnel diffraction integral by representing a given complex function as a finite superposition of complex Gaussians. Once an accurate representation of these functions is attained, it is possible to find analytically its diffraction pattern. There are two useful consequences of this representation: first, the analytical results may be used for further theoretical studies and second, it may be used as a versatile and accurate numerical diffraction technique. The use of the technique is illustrated by calculating the intensity distribution in a vicinity of the focal region of an aberrated converging spherical wave emerging from a circular aperture.


Health service accessibility and deaths from asthma in 401 local authority districts in England and Wales, 1988-92.
The possible contribution of health service accessibility to asthma mortality has not previously been studied in the UK. Using regression analysis, the relationship between geographical isolation from large acute hospital services and mortality from asthma for 401 local authority districts in England and Wales was examined for the period 1988-92. Asthma mortality was found to be strongly associated with the proportion of district households where the head was of social class 4 or 5 (adjusted relative risk 1.61, 95% confidence interval (CI) 1.12 to 2.33), and the proportion of households without access to a car (adjusted relative risk 1.59, 95% CI 0.97 to 2.62). After controlling for these factors, there was a tendency for mortality to rise with increasing distance from hospital, with a relative risk of 1.01 for an increase in distance of one kilometre (95% CI 1.00 to 1.02). The findings suggest that problems of accessibility of care may mean that the control of asthma amongst sufferers living in districts most remote from major health service units might be less than optimal, and this could result in a number of potentially avoidable deaths.