Feline Calicivirus Infection Disrupts Assembly of Cytoplasmic Stress Granules and Induces G3BP1 Cleavage.
In response to stress such as virus infection, cells can stall translation by storing mRNAs away in cellular compartments called stress granules (SGs). This defense mechanism favors cell survival by limiting the use of energy and nutrients until the stress is resolved. In some cases it may also block viral propagation as viruses are dependent on the host cell resources to produce viral proteins. Human norovirus is a member of the Caliciviridae family responsible for gastroenteritis outbreaks worldwide. Previous studies on caliciviruses have identified mechanisms by which they can usurp the host translational machinery, using the viral protein genome-linked VPg, or regulate host protein synthesis through the mitogen-activated protein kinase (MAPK) pathway. Here, we examined the effect of feline calicivirus (FCV) infection on SG accumulation. We show that FCV infection impairs the assembly of SGs despite an increased phosphorylation of eukaryotic initiation factor eIF2α, a hallmark of stress pathway activation. Furthermore, SGs did not accumulate in FCV-infected cells that were stressed with arsenite or hydrogen peroxide. FCV infection resulted in the cleavage of the SG-nucleating protein Ras-GTPase activating SH3 domain-binding protein (G3BP1), which is mediated by the viral 3C-like proteinase NS6(Pro) Using mutational analysis, we identified the FCV-induced cleavage site within G3BP1, which differs from the poliovirus 3C proteinase cleavage site previously identified. Finally, we showed that NS6(Pro)-mediated G3BP1 cleavage impairs SG assembly. In contrast, murine norovirus (MNV) infection did not impact arsenite-induced SG assembly or G3BP1 integrity, suggesting that related caliciviruses have distinct effects on the stress response pathway. Human noroviruses are a major cause of viral gastroenteritis, and it is important to understand how they interact with the infected host cell. Feline calicivirus (FCV) and murine norovirus (MNV) are used as models to understand norovirus biology. Recent studies have suggested that the assembly of stress granules is central in orchestrating stress and antiviral responses to restrict viral replication. Overall, our study provides the first insight on how caliciviruses impair stress granule assembly by targeting the nucleating factor G3BP1 via the viral proteinase NS6(Pro) This work provides new insights into host-pathogen interactions that regulate stress pathways during FCV infection.


Early interventions to prevent disability for workers with mental health conditions: impacts from the DMIE.
As of 2011, over 9 million working-age adults were receiving federal disability benefits and this number is expected to rise steadily. Early intervention programs that seek to maintain employment and forestall the receipt of federal disability benefits offer a promising strategy to reduce the growing number of working-age adults on the disability rolls. Using random assignment, this study examined whether an early intervention program of personal navigators, enhanced medical care, and employment supports can reduce dependence on federal disability benefits for adult workers with mental health conditions. The study reports multivariate and descriptive findings based on 2279 participants in the Demonstration to Maintain Independence and Employment (DMIE). Logistic regression analysis was used to estimate program impacts in the treatment group relative to the control group. Data were integrated from state participant surveys and the SSA Ticket Research File. The DMIE intervention significantly reduced the percent of participants who received disability benefits after 12 months of enrollment. Across both states, the difference between the treatment group and control group was 1.1 percentage points (2.5% versus 3.6%, p < 0.01). In Texas, the difference was 1.2 percentage points (3.2% versus 4.4%, p < 0.01). Early intervention programs with a personal navigator can reduce dependence on federal disability benefits for adult workers with mental health conditions. Future studies on the cost-effectiveness of such programs are needed.


Honorary authorship in health sciences: a protocol for a systematic review of survey research.
Honorary authorship refers to the practice of naming an individual who has made little or no contribution to a publication as an author. Honorary authorship inflates the output estimates of honorary authors and deflates the value of the work by authors who truly merit authorship. This manuscript presents the protocol for a systematic review that will assess the prevalence of five honorary authorship issues in health sciences. Surveys of authors of scientific publications in health sciences that assess prevalence estimates will be eligible. No selection criteria will be set for the time point for measuring outcomes, the setting, the language of the publication, and the publication status. Eligible manuscripts are searched from inception onwards in PubMed, Lens.org , and Dimensions.ai. Two calibrated authors will independently search, determine eligibility of manuscripts, and conduct data extraction. The quality of each review outcome for each eligible manuscript will be assessed with a 14-item checklist developed and piloted for this review. Data will be qualitatively synthesized and quantitative syntheses will be performed where feasible. Criteria for precluding quantitative syntheses were defined a priori. The pooled random effects double arcsine transformed summary event rates of five outcomes on honorary authorship issues with the pertinent 95% confidence intervals will be calculated if these criteria are met. Summary estimates will be displayed after back-transformation. Stata software (Stata Corporation, College Station, TX, USA) version 16 will be used for all statistical analyses. Statistical heterogeneity will be assessed using Tau2 and Chi2 tests and I2 to quantify inconsistency. The outcomes of the planned systematic review will give insights in the magnitude of honorary authorship in health sciences and could direct new research studies to develop and implement strategies to address this problem. However, the validity of the outcomes could be influenced by low response rates, inadequate research design, weighting issues, and recall bias in the eligible surveys. This protocol was registered a priori in the Open Science Framework (OSF) link: https://osf.io/5nvar/ .


Longitudinal evaluation of serum pancreatic enzymes and ultrasonographic findings in diabetic cats without clinically relevant pancreatitis at diagnosis.
Cats with diabetes mellitus can have subclinical pancreatitis but prospective studies to confirm this are lacking. Metabolic control of diabetic cats with pancreatitis is difficult. Subclinical pancreatitis occurs in diabetic cats at the time diabetes is diagnosed or might develop during the follow-up period, hampering diabetic remission. Thirty cats with newly diagnosed diabetes without clinical signs of pancreatitis on admission. Prospective study. On admission and 2 and 6 months later, serum Spec fPL and DGGR-lipase were measured and the pancreas underwent ultrasonographic examination. Pancreatitis was suspected if serum markers were increased or ≥2 ultrasonographic abnormalities were detected. Cats were treated with insulin glargine and diabetic remission was defined as euglycemia ≥4 weeks after discontinuation of insulin. Nonparametric statistical tests were used for analysis. Subclinical pancreatitis at the time of diagnosis was suspected in 33, 50, and 31% of cats based on Spec fPL, DGGR-lipase and ultrasonography, respectively; and in 60% when diagnostic criteria were combined. During the follow-up period, suspected pancreatitis developed in additional 17-30% cats. Only 1 cat had transient clinical signs compatible with pancreatitis. Seventeen of the 30 cats (57%) achieved remission. Frequency of abnormal Spec fPL and DGGR-lipase and abnormal ultrasonographic findings did not differ in cats achieving remission and those who did not. Cats achieving remission had significantly lower Spec fPL at 2 months (P < .001). Based on laboratory and ultrasonographic measurements, many cats with diabetes might have pancreatitis, although without clinical signs. Cats with high Spec fPL might have a reduced chance of diabetic remission; however, this topic needs further studies in large cohorts of diabetic cats.


The risk of cervical atypia in oral contraceptive users.
The interactions of oral contraceptive (OC) use, risk of human papillomavirus (HPV) infection and associated cellular atypia are complex. We investigated the association between history of OC-use, and cytological or histopathological abnormalities in a cohort of non-HPV vaccinated originally 16-17-year-old women participating the PATRICIA trial for 4 years. The total number of hepatitis A-virus (control) vaccine recipients participating in the clinical PATRICIA trial in Finland was 2399. Nine-hundred and ninety-nine women returned questionnaires on living conditions-life habits and sexual health after completing the study. Mean age at answering the questionnaire at the end of the clinical trial was 22 years. Age at sexual debut varied between 12 and 16 years for majority of the women. Cervical cytological samples were obtained every 6 months throughout the PATRICIA trial. The relative risk of cervical atypia associated with time since start of oral contraceptives use was calculated as odds ratio (OR) with 95% confidence interval (CI) using logistic regression. Compared to never-users, the smoking and age-at-sexual-debut adjusted relative risk of cervical intraepithelial neoplasia grade 1 (CIN1) in women who had started the use of oral contraceptives for more than 1 year was low (OR 0.2, 95% CI: 0.1-0.7). Risk of cytological atypia was also reduced (OR 0.6) albeit not significantly (95% CI: 0.3-1.3). Use of oral contraceptives does not increase the risk of cervical atypia but when established might instead be protective.


Advanced practice providers and children's hospital-based pediatric otolarynology practices.
Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting. Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice. A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale. The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.


Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging.
Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit 1 to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MD compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stem fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences.


Navigation-related structural change in the hippocampi of taxi drivers.
Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills. It seems that there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental demands.


Self-assembly of a silicon-containing side-chain liquid crystalline block copolymer in bulk and in thin films: kinetic pathway of a cylinder to sphere transition.
The self-assembly of a high-χ silicon-containing side-chain liquid crystalline block copolymer (LC BCP) in bulk and in thin films is reported, and the structural transition process from the hexagonally packed cylinder (HEX) to the body-centered cubic structure (BCC) in thin films was examined by both reciprocal and real space experimental methods. The block copolymer, poly(dimethylsiloxane-b-11-(4'-cyanobiphenyl-4-yloxy)undecylmethacrylate) (PDMS-b-P(4CNB11C)MA) with a molecular weight of 19.5 kg mol-1 and a volume fraction of PDMS 27% self-assembled in bulk into a hierarchical nanostructure of sub-20 nm HEX cylinders of PDMS with the P(4CNB11C)MA block exhibiting a smectic LC phase with a 1.61 nm period. The structure remained HEX as the P(4CNB11C)MA block transformed to an isotropic phase at ∼120 °C. In the thin films, the PDMS cylindrical microdomains were oriented in layers parallel to the substrate surface. The LC block formed a smectic LC phase which transformed to an isotropic phase at ∼120 °C, and the microphase-separated nanostructure transformed from HEX to BCC spheres at ∼160 °C. The hierarchical structure as well as the dynamic structural transition of the thin films were characterized using in situ grazing-incidence small-angle X-ray scattering and grazing-incidence wide-angle X-ray scattering. The transient morphologies from the HEX to BCC structure in thin films were captured by scanning electron microscopy and atomic force microscopy, and the transition pathway was described.


First Report of Bacterial Wilt Caused by Ralstonia solanacearum on Ageratum conyzoides in China.
Ageratum conyzoides L. is believed to act as reservoir host for many plant diseases. In June 2011, a 30% incidence of bacterial wilt on A. conyzoides was observed in a field of Rhizoma kaempferiae in Yangchun city of Guangdong province. The initial symptoms were wilting of the apical leaves during the day, which recovered at night. After 4 to 6 days, the leaves became totally necrotic. The basal stems of the diseased plants were blackened and the vascular tissue turned brown. To investigate the disease etiology before understanding the disease link between A. conyzoides and R. kaempferiae, 10 plants with typical wilting symptoms were collected from the field. A total of 10 bacterial isolates were isolated from the vascular tissue of each diseased plant on tripheny tetrazolium chloride (TZC) medium. After incubation at 30°C for 2 days, the plates had large, irregular round, fluidal, white colonies with a pink center. Thirty healthy A. conyzoides plants at the four- to six-leaf growth stage were inoculated by injuring the roots and soaking them in a bacterial suspension (1 × 108 cfu/ml) for 20 min with the 10 bacterial isolates separately, and planted in 10-cm pots with sterile gardening soil in a glasshouse (28 to 35°C). Sterile water was used as a negative control. Five days after inoculation, a few leaves of the inoculated plants began to exhibit wilting. The inoculated plants eventually showed the same symptoms as those in the field. The same bacterium was reisolated from inoculated plants. The 30 negative control plants did not have wilt symptoms. With the same inoculation procedure, the bacterium also caused wilting on tomato (25 of 30), pepper (10 of 30), eggplant (2 of 30), ginger (11 of 15), and R. kaempferiae (8 of 15). Using the universal bacterial 16S rDNA primer set 27f/1541R (3), approximately 1,400 bp-fragments were amplified from the 10 isolates, respectively. The sequences for the 10 fragments (GenBank Accession Nos. JX294065 to JX294074) were identical and had 100% sequence identity with 16S rDNA of R. solanacearum GMI1000 (AL646052). The 10 isolates were able to oxidize disaccharides (lactose, maltose, and cellobiose) and hexose alcohols (mannitol, dulcitol, and sorbitol). According to Hayward's classification, all isolates were biovar 3 (2). Based on the pathogenicity tests, carbohydrate utilization, and near full-length 16S rDNA sequences, the bacterial isolates from the diseased A. conyzoides belonged to race 4 and biovar 3 of R. solanacearum. Furthermore, the specific 280-bp and 140-bp fragments were respectively amplified from all 10 isolates by using the multiplex PCR (1). In addition, specific 165-bp fragments were amplified from all the isolates using the specific primers AKIF/AKIR (3), which indicates the bacterium belongs to R. solanacearum Phylotype I. To our knowledge, this is the first report of a disease caused by R. solanacearum on A. conyzoides in China. References: (1) M. Fegan and P. Prior. Page 449 in: Bacterial Wilt Disease and the Ralstonia solanacearum Species Complex. C. Allen et al., eds. The American Phytopathological Society. St. Paul, MN, 2005. (2) A. C. Hayward. J. Appl. Bacteriol. 27:265, 1964. (3) M. Horita et al. J. Gen. Plant Pathol. 70:278, 2004.


Viral control in chronic HIV-1 subtype C infection is associated with enrichment of p24 IgG1 with Fc effector activity.
Postinfection HIV viral control and immune correlates analysis of the RV144 vaccine trial indicate a potentially critical role for Fc receptor-mediated antibody functions. However, the influence of functional antibodies in clade C infection is largely unknown. Plasma samples from 361 chronic subtype C-infected, antiretroviral therapy-naive participants were tested for their HIV-specific isotype and subclass distributions, along with their Fc receptor-mediated functional potential. Total IgG, IgG subclasses and IgA binding to p24 clade B/C and gp120 consensus C proteins were assayed by multiplex. Antibody-dependent uptake of antigen-coated beads and Fc receptor-mediated natural killer cell degranulation were evaluated as surrogates for antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), respectively. p24 IgG1 was the only subclass associated with viral control (P = 0.01), with higher p24-specific ADCP and ADCC responses detected in individuals with high p24 IgG1. Although p24 IgG1 levels were enriched in patients with elevated Gag-specific T-cell responses, these levels remained an independent predictor of low-viral loads (P = 0.04) and high CD4+ cell counts (P = 0.004) after adjusting for Gag-specific T-cell responses and for protective HLA class I alleles. p24 IgG1 levels independently predict viral control in HIV-1 clade C infection. Whether these responses contribute to direct antiviral control via the recruited killing of infected cells via the innate immune system or simply mark a qualitatively superior immune response to HIV, is uncertain, but highlights the role of p24-specific antibodies in control of clade C HIV-1 infection.


Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes.
Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases.


Comparative mapping of X chromosomes in vole species of the genus Microtus.
Comparative mapping of X-linked genes has progressed rapidly since Ohno's prediction that genes on the X chromosome should be conserved as a syntenic group in all mammals. Although several conserved blocks of homology between human and mouse have been discovered, rearrangements within the X chromosome have also been characterized. More recently, some exceptions to Ohno's law have been reported. We have used fluorescence in situ hybridization (FISH) to map five genes, Gla, G6pd, Hprt, Pgk1 and Xist, to two of the largest conserved segments of X material in five members of the genus Microtus (grey vole) and show that vole X chromosomes demonstrate greater homology to human than to mouse. Cytogenetic analysis indicates a relatively high frequency of rearrangement during vole evolution, although certain blocks of homology appear to be highly conserved in all species studied to date. On this basis we were able to predict the probable location of the rat X inactivation centre (Xic) based solely on high-resolution G-banding. Our prediction was then confirmed by mapping the rat Xist gene by FISH. The possible significance of conserving long-range chromosome structure in the vicinity of the Xic is discussed with respect to the mechanism of X inactivation.


A formula to predict spectral domain optical coherence tomography (OCT) retinal nerve fiber layer measurements based on time domain OCT measurements.
To establish and validate a formula to predict spectral domain (SD)-optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness from time domain (TD)-OCT RNFL measurements and other factors. SD-OCT and TD-OCT scans were obtained on the same day from healthy participants and patients with glaucoma. Univariate and multivariate linear regression relationships were analyzed to convert average Stratus TD-OCT measurements to average Cirrus SD-OCT measurements. Additional baseline characteristics included age, sex, intraocular pressure, central corneal thickness, spherical equivalent, anterior chamber depth, optic disc area, visual field (VF) mean deviation, and pattern standard deviation. The formula was generated using a training set of 220 patients and then evaluated on a validation dataset of 105 patients. The training set included 71 healthy participants and 149 patients with glaucoma. The validation set included 27 healthy participants and 78 patients with glaucoma. Univariate analysis determined that TD-OCT RNFL thickness, age, optic disc area, VF mean deviation, and pattern standard deviation were significantly associated with SD-OCT RNFL thickness. Multivariate regression analysis using available variables yielded the following equation: SD-OCT RNFL = 0.746 × TD-OCT RNFL + 17.104 (determination coefficient [R(2)] = 0.879). In the validation sample, the multiple regression model explained 85.6% of the variance in the SD-OCT RNFL thickness. The proposed formula based on TD-OCT RNFL thickness may be useful in predicting SD-OCT RNFL thickness. Other factors associated with SD-OCT RNFL thickness, such as age, disc area, and mean deviation, did not contribute to the accuracy of the final equation.


Characterization of the pigmented shell-forming proteome of the common grove snail Cepaea nemoralis.
With a diversity of pigmented shell morphotypes governed by Mendelian patterns of inheritance, the common grove snail, Cepaea nemoralis, has served as a model for evolutionary biologists and population geneticists for decades. Surprisingly, the molecular mechanisms by which C. nemoralis generates this pigmented shelled diversity, and the degree of evolutionary conservation present between molluscan shell-forming proteomes, remain unknown. Here, using next generation sequencing and high throughput proteomics, we identify and characterize the major proteinaceous components of the C. nemoralis shell, the first shell-proteome for a pulmonate mollusc. The recent availability of several marine molluscan shell-proteomes, and the dataset we report here, allow us to identify 59 evolutionarily conserved and novel shell-forming proteins. While the C. nemoralis dataset is dominated by proteins that share little to no similarity with proteins in public databases, almost half of it shares similarity with proteins present in other molluscan shells. In addition, we could not find any indication that a protein (or class of proteins) is directly associated with shell pigmentation in C. nemoralis. This is in contrast to the only other partially characterized molluscan-shell pigmentation mechanism employed by the tropical abalone Haliotis asinina. The unique pulmonate shell-forming proteome that we report here reveals an abundance of both mollusc-specific and pulmonate-specific proteins, suggesting that novel coding sequences, and/or the extensive divergence of these sequences from ancestral sequences, supported the innovation of new shell types within the Conchifera. In addition, we report here the first evidence that molluscs use independently evolved mechanisms to pigment their shells. This proteome provides a solid foundation from which further studies aimed at the functional characterization of these shell-forming proteins can be conducted.


MAP 1C is a microtubule-activated ATPase which translocates microtubules in vitro and has dynein-like properties.
We observe that one of the high molecular mass microtubule-associated proteins (MAPs) from brain exhibits nucleotide-dependent binding to microtubules. We identify the protein as MAP IC, which was previously described in this laboratory as a minor component of standard microtubule preparations (Bloom, G.S., T. Schoenfeld, and R.B. Vallee, 1984, J. Cell Biol., 98:320-330). We find that MAP 1C is enriched in microtubules prepared in the absence of nucleotide. Kinesin is also found in these preparations, but can be specifically extracted with GTP. A fraction highly enriched in MAP 1C can be prepared by subsequent extraction of the microtubules with ATP. Two activities cofractionate with MAP 1C upon further purification, a microtubule-activated ATPase activity and a microtubule-translocating activity. These activities indicate a role for the protein in cytoplasmic motility. MAP 1C coelectrophoreses with the beta heavy chain of Chlamydomonas flagellar dynein, and has a sedimentation coefficient of 20S. Exposure to ultraviolet light in the presence of vanadate and ATP results in the production of two large fragments of MAP 1C. These characteristics suggest that MAP 1C may be a cytoplasmic analogue of axonemal dynein.


Red blood cells ageing markers: a multi-parametric analysis.
Red blood cells collected in citrate-phosphate-dextrose can be stored for up to 42 days at 4 °C in saline-adenine-glucose-mannitol additive solution. During this controlled, but nevertheless artificial, ex vivo ageing, red blood cells accumulate lesions that can be reversible or irreversible upon transfusion. The aim of the present study is to follow several parameters reflecting cell metabolism, antioxidant defences, morphology and membrane dynamics during storage. Five erythrocyte concentrates were followed weekly during 71 days. Extracellular glucose and lactate concentrations, total antioxidant power, as well as reduced and oxidised intracellular glutathione levels were quantified. Microvesiculation, percentage of haemolysis and haematologic parameters were also evaluated. Finally, morphological changes and membrane fluctuations were recorded using label-free digital holographic microscopy. The antioxidant power as well as the intracellular glutathione concentration first increased, reaching maximal values after one and two weeks, respectively. Irreversible morphological lesions appeared during week 5, where discocytes began to transform into transient echinocytes and finally spherocytes. At the same time, the microvesiculation and haemolysis started to rise exponentially. After six weeks (expiration date), intracellular glutathione was reduced by 25%, reflecting increasing oxidative stress. The membrane fluctuations showed decreased amplitudes during shape transition from discocytes to spherocytes. Various types of lesions accumulated at different chemical and cellular levels during storage, which could impact their in vivo recovery after transfusion. A marked effect was observed after four weeks of storage, which corroborates recent clinical data. The prolonged follow-up period allowed the capture of deep storage lesions. Interestingly, and as previously described, the severity of the changes differed among donors.


Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters.
To explore the global mechanisms of estrogen-regulated transcription, we used chromatin immunoprecipitation coupled with DNA microarrays to determine the localization of RNA polymerase II (Pol II), estrogen receptor alpha (ERalpha), steroid receptor coactivator proteins (SRC), and acetylated histones H3/H4 (AcH) at estrogen-regulated promoters in MCF-7 cells with or without estradiol (E2) treatment. In addition, we correlated factor occupancy with gene expression and the presence of transcription factor binding elements. Using this integrative approach, we defined a set of 58 direct E2 target genes based on E2-regulated Pol II occupancy and classified their promoters based on factor binding, histone modification, and transcriptional output. Many of these direct E2 target genes exhibit interesting modes of regulation and biological activities, some of which may be relevant to the onset and proliferation of breast cancers. Our studies indicate that about one-third of these direct E2 target genes contain promoter-proximal ERalpha-binding sites, which is considerably more than previous estimates. Some of these genes represent possible novel targets for regulation through the ERalpha/AP-1 tethering pathway. Our studies have also revealed several previously uncharacterized global features of E2-regulated gene expression, including strong positive correlations between Pol II occupancy and AcH levels, as well as between the E2-dependent recruitment of ERalpha and SRC at the promoters of E2-stimulated genes. Furthermore, our studies have revealed new mechanistic insights into E2-regulated gene expression, including the absence of SRC binding at E2-repressed genes and the presence of constitutively bound, promoter-proximally paused Pol IIs at some E2-regulated promoters. These mechanistic insights are likely to be relevant for understanding gene regulation by a wide variety of nuclear receptors.


[Immunophenotypic analysis in acute leukemia].
Acute leukemias have been classified on French-American-British (FAB) criteria depending on the morphocytochemical features of blasts. Immunophenotyping and clonal rearrangement analysis of lineage-associated genes can decide a frozen stage of the hematopoietic differentiation process in blasts from acute leukemias. B-lineage acute lymphoblastic leukemia (ALL) and T-lineage ALL are systematically classified according to the sequential expression of differentiation-associated antigens. In acute myelogenous leukemia (AML), several new entities are proposed: AML-M0 is an AML without cytologic maturation, in which the myeloid commitment should be demonstrated by myeloperoxidase-positive microgranule on immunohistochemical staining or electron-microscopy, or by positive reaction for CD13 or CD33 antigens. CD7-positive AML is considered to be one of immature subtypes of AML, rather than hybrid leukemia. Thus, immunological studies on blasts enable us to discriminate a subgroup of leukemias, which will perhaps contribute to the improvement of treatment approach.


HIV and diarrhea in the era of HAART: 1998 New York State hospitalizations.
This study reflects an attempt to identify the causes of diarrheal illness in hospitalized HIV patients in light of therapeutic advancements in HIV management. The study identifies the various etiologies associated with diarrhea among HIV patients hospitalized in New York State in 1998. Data for this study were extracted from the New York State Department of Health Statewide Planning and Research Cooperative System. Pathogens recognized to cause diarrhea in persons with HIV and general codes identifying diarrhea were examined by using the principal and all secondary diagnoses based on the International Classification of Diseases 9th Revision Clinical Modification codes. Based on the Statewide Planning and Research Cooperative System data set, more than 15,000 patients with HIV were hospitalized in 1998. Among the HIV patients hospitalized, 2.8% were admitted with a diarrheal diagnosis. The following diagnoses occurred the most frequently among HIV patients hospitalized with a diarrheal illness: Clostridium difficile (51.3%), other protozoal diseases (18.1%), and other organisms, not elsewhere specified (11.7%). In the era of highly active antiretroviral therapy, diarrhea is still an occurring symptom in HIV patients. Despite the relatively small percentage of hospitalizations attributed to diarrhea, clinicians must remember that even "mild" to "moderate" diarrhea can have a debilitating impact among persons with the symptom.


Using mental imagery to improve memory in patients with Alzheimer disease: trouble generating or remembering the mind's eye?
This study was conducted to understand whether patients with mild Alzheimer disease (AD) could use general or self-referential mental imagery to improve their recognition of visually presented words. Experiment 1 showed that, unlike healthy controls, patients generally did not benefit from either type of imagery. To help determine whether the patients' inability to benefit from mental imagery at encoding was due to poor memory or due to an impairment in mental imagery, participants performed 4 imagery tasks with varying imagery and cognitive demands. Experiment 2 showed that patients successfully performed basic visual imagery, but degraded semantic memory, coupled with visuospatial and executive functioning deficits, impaired their ability to perform more complex types of imagery. Given that patients with AD can perform basic mental imagery, our results suggest that episodic memory deficits likely prevent AD patients from storing or retrieving general mental images generated during encoding. Overall, the results of both experiments suggest that neurocognitive deficits do not allow patients with AD to perform complex mental imagery, which may be most beneficial to improving memory. However, our data also suggest that intact basic mental imagery and rehearsal could possibly be helpful if used in a rehabilitation multisession intervention approach.


Sex-specific differences in metabolic control, cardiovascular risk, and interventions in patients with type 2 diabetes mellitus.
Sex-specific differences appear particularly relevant in the management of type 2 diabetes mellitus (T2DM), with women experiencing greater increases in cardiovascular morbidity and mortality than do men. The aim of this article was to investigate the influence of biological sex on clinical care and microvascular and macrovascular complications in patients with T2DM in a Central European university diabetes clinic. In a cross-sectional study, sex-specific disparities in metabolic control, cardiovascular risk factors, and diabetic complications, as well as concomitant medication use and adherence to treatment recommendations, were evaluated in 350 consecutive patients who were comparable for age, diabetes duration, and body mass index. Study inclusion criteria included age ≤75 years, T2DM, a documented history of presence or absence of coronary heart disease (CHD), and informed consent. Patients were followed in the diabetes outpatient clinic between November 2007 and March 2008. Two hundred and one patients with T2DM met inclusion criteria (93 [46.3%] women, 108 [53.7%] men). Women with T2DM had higher mean (SE) systolic blood pressure (155.4 [22.5] vs 141.0 [19.8] mm Hg for men; P < 0.001) and total cholesterol (TC) (5.28 [1.34] vs 4.86 [1.29] mmol/L for men; P < 0.05), but a lower TC:HDL-C ratio (4.1 [1.19] vs 4.5 [1.2] for men; P < 0.05). Slightly more men (32.4%) than women (26.9%) reached the therapeutic goal of <7.0% for glycosylated hemoglobin. Women with shorter diabetes duration (<10 years) received oral antihyperglycemic therapy less frequently (P < 0.05). Women with longer disease duration had hypertension more frequently than did their male counterparts (100% vs 86.0%, respectively; P < 0.01). Despite a similar rate of CHD, men were twice as likely as women to have had coronary interventions (percutaneous transluminal coronary angioplasty/coronary artery bypass graft, 25.0% vs 12.9%, respectively; P < 0.05). Women with CHD also had a higher rate of cerebral ischemia than did men (27.6% vs 5.4%, respectively; P < 0.05) and received aspirin less frequently for secondary prevention (P < 0.001). Men had greater overall adherence to diabetes and cardiovascular risk guidelines than did women (66.4% vs 58.9%, respectively; P < 0.01). In this study of diabetes clinic outpatients, women with T2DM had a worse cardiovascular risk profile and achieved therapeutic goals less frequently than did men. Treatment strategies should be improved in both sexes, but women with diabetes may be in need of more aggressive treatment, especially when cardiovascular disease is present.


Health Inequality among Chinese Older Adults: The Role of Childhood Circumstances.
This paper examines the extent to which childhood circumstances contribute to health inequality in old age and how the contributions may vary across key dimensions of health. We link the China Health and Retirement Longitudinal Study (CHARLS) in 2013 and 2015 with its Life History Survey in 2014 to quantify health inequality due to childhood circumstances for which they have little control. We evaluate comprehensive dimensions of health ranging from cognitive health, mental health, physical health, self-rated health to mortality. Our analytic sample includes about 8,000 Chinese persons age above 60. Using the Shapley value decomposition approach, we first show that childhood circumstances may explain 1-23 percent of health inequality in old age across multiple health outcomes. Second, while both direct health-related circumstances and indirect health-related circumstances contribute significantly to health inequality, the latter tends to be more sizable. Our findings support the value of a life course approach in identifying the key determinants of health in old age.


Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women.
Data are limited on hereditary angioedema (HAE) in pregnant women and the safety and efficacy of therapies for treatment and prevention of HAE attacks during pregnancy. Prospective studies are unlikely given the rarity of HAE and ethical considerations regarding enrollment of pregnant female subjects in clinical trials. A retrospective analysis of clinical trial and compassionate-use data was conducted to identify subjects who received nanofiltered C1 esterase inhibitor (C1 INH-nf; human) during pregnancy. This study evaluates the efficacy and safety of human C1 INH-nf for treatment and prevention of HAE attacks in pregnant women. Data from pregnant subjects enrolled in either open-label extensions of two randomized, double-blind, placebo-controlled trials of C1 INH-nf or in a compassionate-use program were retrospectively analyzed for efficacy (e.g., total attacks, attack frequency during prophylaxis, and monthly attack rates) and safety (e.g., pregnancy outcomes and adverse events). C1 INH-nf was administered as acute treatment, preprocedural prophylaxis, or routine prophylaxis. C1 INH-nf prophylaxis substantially reduced monthly attack rates. Of 16 subjects, 13 delivered 14 healthy neonates (1 set of twins). Two adverse fetal outcomes were reported; neither was considered by the principal investigator to be related to C1 INH-nf. One subject's pregnancy outcome was unknown. This analysis shows a favorable risk-benefit profile for C1 INH-nf for managing HAE during pregnancy. NCT Identifier: NCT00438815; NCT00462709.


Toxicity and kinetics of amitraz in dogs.
To evaluate the toxic effects of amitraz in dogs and their reversal by various doses of atipamezole. 6 male 1-year-old Beagles. Dogs were given 100 mg of amitraz/kg of body weight, PO. Atipamezole was administered at 3 dose rates. Clinical examination and blood sample collection were performed regularly for 48 hours to examine biological parameters and determine the toxicokinetics of amitraz as well as the efficacy of the antidote. A specific high-performance thin layer chromatographic method was developed to determine plasma amitraz concentrations. Clinical signs of toxicosis included sedation, bradycardia, polyuria, hypothermia, and hyperglycemia, all of which could be related to the alpha 2-agonist activity of amitraz, and were reversed by low doses of atipamezole (50 micrograms/kg, IM), a potent alpha 2-antagonist, within 10 minutes after injection. Peak plasma concentrations were observed after 5 hours, and the elimination half-life was long (about 24 hours). All clinical and biological effects observed during the course of amitraz poisoning could be attributed to the parent compound itself and were reversed by low doses of atipamezole. The half-life of amitraz was substantially longer than that in other studies because of the high dose administered. Atipamezole can be administered i.m. to dogs with severe amitraz poisoning to reverse all the effects observed.


The acute effect of flavonoid-rich apples and nitrate-rich spinach on cognitive performance and mood in healthy men and women.
Flavonoids and nitrate in a fruit and vegetable diet may be protective against cardiovascular disease and cognitive decline through effects on nitric oxide (NO) status. The circulating NO pool is increased via distinct pathways by dietary flavonoids and nitrate. Our aim was to investigate the acute effects of apples, rich in flavonoids, and spinach, rich in nitrate, independently and in combination on NO status, cognitive function and mood in a randomised, controlled, cross-over trial with healthy men and women (n = 30). The acute effects of four energy-matched treatments (control, apple, spinach and apple + spinach) were compared. Endpoints included plasma nitric oxide status (determined by measuring S-nitrosothiols + other nitroso species (RXNO)), plasma nitrate and nitrite, salivary nitrate and nitrite, urinary nitrate and nitrite as well as cognitive function (determined using the Cognitive Drug Research (CDR) computerized cognitive assessment battery) and mood. Relative to control, all treatments resulted in higher plasma RXNO. A significant increase in plasma nitrate and nitrite, salivary nitrate and nitrite as well as urinary nitrate and nitrite was observed with spinach and apple + spinach compared to control. No significant effect was observed on cognitive function or mood. In conclusion, flavonoid-rich apples and nitrate-rich spinach augmented NO status acutely with no concomitant improvements or deterioration in cognitive function and mood.


Colonization of Non-biodegradable and Biodegradable Plastics by Marine Microorganisms.
Plastics are ubiquitous in the oceans and constitute suitable matrices for bacterial attachment and growth. Understanding biofouling mechanisms is a key issue to assessing the ecological impacts and fate of plastics in marine environment. In this study, we investigated the different steps of plastic colonization of polyolefin-based plastics, on the first one hand, including conventional low-density polyethylene (PE), additivated PE with pro-oxidant (OXO), and artificially aged OXO (AA-OXO); and of a polyester, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), on the other hand. We combined measurements of physical surface properties of polymers (hydrophobicity and roughness) with microbiological characterization of the biofilm (cell counts, taxonomic composition, and heterotrophic activity) using a wide range of techniques, with some of them used for the first time on plastics. Our experimental setup using aquariums with natural circulating seawater during 6 weeks allowed us to characterize the successive phases of primo-colonization, growing, and maturation of the biofilms. We highlighted different trends between polymer types with distinct surface properties and composition, the biodegradable AA-OXO and PHBV presenting higher colonization by active and specific bacteria compared to non-biodegradable polymers (PE and OXO). Succession of bacterial population occurred during the three colonization phases, with hydrocarbonoclastic bacteria being highly abundant on all plastic types. This study brings original data that provide new insights on the colonization of non-biodegradable and biodegradable polymers by marine microorganisms.


Changes in body composition over 8 years in a randomized trial of a lifestyle intervention: the look AHEAD study.
To determine the effects of an intensive lifestyle intervention versus a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years. Body composition was measured by dual-energy X-ray absorptiometry in a subset of 1019 Look AHEAD study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain ≥7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education. At 1 year, the intervention group lost fat (5.6 ± 0.2 kg) and lean mass (2.3 ± 0.1 kg) but regained fat (∼100%) and lost lean mass between years 1 and 8. Between baseline and year 8, weight loss was greater in intervention versus comparison groups (4.0 ± 0.4 vs. 2.3 ± 0.4 kg); comparison group weight loss was mostly lean mass (2.1 ± 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post-baseline time points. Reduced fat mass may place the intervention group at a lower risk of obesity-linked sequelae, a hypothesis that can be tested by future studies of this cohort.


Decoding gripping force based on local field potentials recorded from subthalamic nucleus in humans.
The basal ganglia are known to be involved in the planning, execution and control of gripping force and movement vigour. Here we aim to define the nature of the basal ganglia control signal for force and to decode gripping force based on local field potential (LFP) activities recorded from the subthalamic nucleus (STN) in patients with deep brain stimulation (DBS) electrodes. We found that STN LFP activities in the gamma (55-90 Hz) and beta (13-30m Hz) bands were most informative about gripping force, and that a first order dynamic linear model with these STN LFP features as inputs can be used to decode the temporal profile of gripping force. Our results enhance the understanding of how the basal ganglia control gripping force, and also suggest that deep brain LFPs could potentially be used to decode movement parameters related to force and movement vigour for the development of advanced human-machine interfaces.


The effect of exercise on uteroplacental Doppler waveforms in normal and complicated pregnancies.
Animal studies have suggested a detrimental effect of exercise on uterine blood flow, but it is unclear whether the same responses occur in human pregnancy. Thirty-four women in the third trimester of singleton pregnancies underwent a bicycle exercise test during which a pulsed Doppler method was used to assess the response of the uteroplacental circulation. Twelve pregnancies were uncomplicated and the other 22 were complicated by hypertension, small for gestational age (SGA) fetus, or both. Exercise appeared to increase the pulsatility of the uteroplacental Doppler waveform in all cases. The changes in the waveforms were more exaggerated in the complicated pregnancies, particularly when the resting waveform had been abnormal. These changes indicate an increase in uteroplacental vascular resistance with exercise, suggesting a deleterious effect of physical exertion in the third trimester, particularly in the presence of hypertension or SGA fetus.


NMR study of the galactomannans of Trichophyton mentagrophytes and Trichophyton rubrum.
Around 90% of chronic dermatophyte infections are caused by the fungi Trichophyton mentagrophytes and Trichophyton rubrum. One of the causes of the chronic infection resides in the immunosuppressive effects of the cell-wall components of these organisms. Therefore we have attempted to identify the chemical structure of galactomannan, one of the major cell-wall components. The cell-wall polysaccharides secreted by T. mentagrophytes and T. rubrum were isolated from the culture medium and fractionated into three subfractions by DEAE-Sephadex chromatography. Analysis of each subfraction by NMR indicated that there are two kinds of polysaccharides present, i.e. mannan and galactomannan. The mannan has a linear backbone consisting of alpha1,6-linked mannose units, with alpha1,2-linked mannose units as side chains. The core mannan moiety of the galactomannan was analysed by a sequential NMR assignment method after removing the galactofuranose units by acid treatment. The result indicates that the mannan moiety has a linear repeating structure of alpha1,2-linked mannotetraose units connected by an alpha1,6 linkage. The H-1 signals of the two intermediary alpha1, 2-linked mannoses of the tetraose unit showed a significant upfield shift (Deltadelta=0.05-0.08 p.p.m.), due to the steric effect of an alpha1,6-linked mannose unit. The attachment point of the galactofuranose units was determined at C-3 of the core mannan by the assignment of the downfield-shifted 13C signals of the galactomannan compared with those of the acid-modified product. In these galactomannans there were no polygalactofuranosyl chains which have been found in Penicillium charlesii and Aspergillus fumigatus.


Biomimetic Concealing of PLGA Microspheres in a 3D Scaffold to Prevent Macrophage Uptake.
Scaffolds functionalized with delivery systems for the release of growth factors is a robust strategy to enhance tissue regeneration. However, after implantation, macrophages infiltrate the scaffold, eventually initiating the degradation and clearance of the delivery systems. Herein, it is hypothesized that fully embedding the poly(d,l-lactide-co-glycolide acid) microspheres (MS) in a highly structured collagen-based scaffold (concealing) can prevent their detection, preserving the integrity of the payload. Confocal laser microscopy reveals that non-embedded MS are easily internalized; when concealed, J774 and bone marrow-derived macrophages (BMDM) cannot detect them. This is further demonstrated by flow cytometry, as a tenfold decrease is found in the number of MS engulfed by the cells, suggesting that collagen can cloak the MS. This correlates with the amount of nitric oxide and tumor necrosis factor-α produced by J774 and BMDM in response to the concealed MS, comparable to that found for non-functionalized collagen scaffolds. Finally, the release kinetics of a reporter protein is preserved in the presence of macrophages, only when MS are concealed. The data provide detailed strategies for fabricating three dimensional (3D) biomimetic scaffolds able to conceal delivery systems and preserve the therapeutic molecules for release.


1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain.
We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-type over L-type calcium channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-type channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Cav3.2 over Cav1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Cav3.2 channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Cav3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies.


Measurement properties of instruments evaluating self-care and related concepts in people with chronic obstructive pulmonary disease: A systematic review.
The use of valid and reliable instruments for assessing self-care is crucial for the evaluation of chronic obstructive pulmonary disease (COPD) management programs. The aim of this review is to evaluate the measurement properties and theoretical foundations of instruments for assessing self-care and related concepts in people with COPD. A systematic review was conducted of articles describing the development and validation of self-care instruments. The methodological quality of the measurement properties was assessed using the COSMIN checklist. Ten studies were included evaluating five instruments: three for assessing self-care and self-management and two for assessing self-efficacy. The COPD Self-Efficacy Scale was the most studied instrument, but due to poor study methodological quality, evidence about its measurement properties is inconclusive. Evidence from the COPD Self-Management Scale is more promising, but only one study tested its properties. Due to inconclusive evidence of their measurement properties, no instrument can be recommended for clinical use.


Mandibular overdentures stabilized by Astra Tech implants with either ball attachments or magnets: 5-year results.
The purpose of this work was to report on the use of implant-stabilized overdentures in the mandible using the Astra Tech implant system with either ball attachments or magnets as the retentive mechanism. Mandibular overdentures that used ball attachments on 2 implants were provided for 13 edentulous patients; 12 edentulous patients were provided with mandibular overdentures with magnet retention, using 2 implants in 10 patients and 3 implants in 2 patients. Once they were comfortable, the participants were placed on annual recall. Any other visits were initiated by the patients. Detailed records were kept for all visits. At the annual recall the following parameters were monitored: plaque levels, mucosal health, marginal bone levels, and the patients' assessment of the treatment. The patients were followed for 5 years. There was no statistical difference between the 2 groups for mucosal health and postinsertion maintenance. The magnet group had more abutment surfaces covered with plaque. Statistical analysis of the patients' subjective assessment of their treatment showed that the magnet group was less comfortable and chewing was less effective. The results indicate that both ball attachments and magnets used on isolated Astra Tech implants in the mandible are viable treatment options. Both attachment mechanisms provided patient satisfaction, although the ball attachments were better in this respect than the magnets.


Campylobacter epidemiology: a descriptive study reviewing 1 million cases in England and Wales between 1989 and 2011.
To review Campylobacter cases in England and Wales over 2 decades and examine the main factors/mechanisms driving the changing epidemiology. A descriptive study of Campylobacter patients between 1989 and 2011. Cases over 3 years were linked anonymously to postcode, population density, deprivation indices and census data. Cases over 5 years were anonymously linked to local weather exposure estimates. Patients were from general practice, hospital and environmental health investigations through primary diagnostic laboratories across England and Wales. There were 1 109 406 cases. Description of changes in Campylobacter epidemiology over 23 years and how the main drivers may influence these. There was an increase in Campylobacter cases over the past 23 years, with the largest increase in people over 50 years. Changes in the underlying population have contributed to this, including the impacts of population increases after World War I, World War II and the 'baby boom' of the 1960s. A recent increase in risk or ascertainment within this population has caused an increase in cases in all age groups from 2004 to 2011. The seasonal increase in cases between weeks 18 (Early May) and 22 (Early June) was consistent across ages, years and regions and was most marked in children and in more rural regions. Campylobacter prevalence by week in each region correlated with temperature 2 weeks before. There were higher prevalences in areas with a low population density, low deprivation and lower percentage of people of ethnic origin. Data from sero-phage and multilocus sequence typing show a few common types and many uncommon types. The drivers/mechanisms influencing seasonality, age distribution, population density, socioeconomic and long-term differences are diverse and their relative contributions remain to be established. Surveillance and typing provide insights into Campylobacter epidemiology and sources of infection, providing a sound basis for targeted interventions.


Promoting exercise behavior in older adults: using a cognitive behavioral intervention.
Health benefits associated with exercise are only obtained when exercise is maintained. The purpose of this pilot study was to examine the effects of a cognitive behavioral therapy (CBT) intervention on exercise behavior and physical outcomes in older adults. All participants were taught progressive flexibility, strength, and endurance exercises. The control group received no additional treatment. The experimental group was taught to recognize negative thoughts related to exercise and to counter these thoughts with more positive ones. Subsequent exercise behavior and physical outcomes were measured in all participants. Cognitive behavioral therapy was moderately to largely effective in improving the majority of physical outcomes assessed. In addition, CBT was moderately effective in improving several components of self-reported exercise behavior and mildly effective in improving exercise behavior overall. Results suggest that nurses can train older adults to identify and modify thoughts that interfere with or reduce their exercise behavior and thus improve physical functioning.


Osmotic avoidance in Caenorhabditis elegans: synaptic function of two genes, orthologues of human NRXN1 and NLGN1, as candidates for autism.
Neurexins and neuroligins are cell adhesion molecules present in excitatory and inhibitory synapses, and they are required for correct neuron network function. These proteins are found at the presynaptic and postsynaptic membranes. Studies in mice indicate that neurexins and neurologins have an essential role in synaptic transmission. Recent reports have shown that altered neuronal connections during the development of the human nervous system could constitute the basis of the etiology of numerous cases of autism spectrum disorders. Caenorhabditis elegans could be used as an experimental tool to facilitate the study of the functioning of synaptic components, because of its simplicity for laboratory experimentation, and given that its nervous system and synaptic wiring has been fully characterized. In C. elegans nrx-1 and nlg-1 genes are orthologous to human NRXN1 and NLGN1 genes which encode alpha-neurexin-1 and neuroligin-1 proteins, respectively. In humans and nematodes, the organization of neurexins and neuroligins is similar in respect to functional domains. The head of the nematode contains the amphid, a sensory organ of the nematode, which mediates responses to different stimuli, including osmotic strength. The amphid is made of 12 sensory bipolar neurons with ciliated dendrites and one presynaptic terminal axon. Two of these neurons, named ASHR and ASHL are particularly important in osmotic sensory function, detecting water-soluble repellents with high osmotic strength. The dendrites of these two neurons lengthen to the tip of the mouth and the axons extend to the nerve ring, where they make synaptic connections with other neurons determining the behavioral response. To evaluate the implications of neurexin and neuroligin in high osmotic strength avoidance, we show the different response of C. elegans mutants defective in nrx-1 and nlg-1 genes, using a method based on a 4M fructose ring. The behavioral phenotypes were confirmed using specific RNAi clones. In C. elegans, the dsRNA required to trigger RNAi can be administered by feeding. The delivery of dsRNA through food induces the RNAi interference of the gene of interest thus allowing the identification of genetic components and network pathways.


Segmental structure in banded mongoose calls.
In complex animal vocalizations, such as bird or whale song, a great variety of songs can be produced via rearrangements of a smaller set of 'syllables', known as 'phonological syntax' or 'phonocoding' However, food or alarm calls, which function as referential signals, were previously thought to lack such combinatorial structure. A new study of calls in the banded mongoose Mungos mungo provides the first evidence of phonocoding at the level of single calls. The first portion of the call provides cues to the identity of the caller, and the second part encodes its current activity. This provides the first example known in animals of something akin to the consonants and vowels of human speech.


Representational momentum in vision and touch: Visual motion information biases tactile spatial localization.
After an object disappears, the vanishing point is shifted in the direction of motion, a phenomenon known as representational momentum. The present study focused on the relationship between motion information and spatial location in a crossmodal setting. In two visuotactile experiments, we studied how motion information in one sensory modality affects the perceived final location of a motion signal (congruent vs. incongruent left-right motion direction) in another modality. The results revealed a unidirectional crossmodal influence of motion information on spatial localization performance. While visual motion information influenced the perceived final location of the tactile stimulus, tactile motion information had no influence on visual localization. These results therefore extend the existing literature on crossmodal influences on spatial location and are discussed in relation to current theories of multisensory perception.


An integrative genomics approach to infer causal associations between gene expression and disease.
A key goal of biomedical research is to elucidate the complex network of gene interactions underlying complex traits such as common human diseases. Here we detail a multistep procedure for identifying potential key drivers of complex traits that integrates DNA-variation and gene-expression data with other complex trait data in segregating mouse populations. Ordering gene expression traits relative to one another and relative to other complex traits is achieved by systematically testing whether variations in DNA that lead to variations in relative transcript abundances statistically support an independent, causative or reactive function relative to the complex traits under consideration. We show that this approach can predict transcriptional responses to single gene-perturbation experiments using gene-expression data in the context of a segregating mouse population. We also demonstrate the utility of this approach by identifying and experimentally validating the involvement of three new genes in susceptibility to obesity.


[Methodological problems associated with the planning of.].
Cluster randomization, where groups (or clusters) of subjects, rather than single individuals, are randomly allocated to intervention groups, is increasingly being adopted in studies to evaluate interventions directed at a whole area or healthcare unit (such as a hospital ward, or a medical practice). Studies that use this method of randomization are referred to as cluster randomized trials (CRT) and have considerable organizational and economic advantages. However, CRTs have distinctive ethical issues that need to be considered and most importantly, require a series of methodological modifications during data analysis and calculation of sample size (during which additional parameters, such as the intracluster correlation coefficient and the design effect, need to be obtained). Methodological guidelines for conducting CRTs have been published in November 2002. However, no scientific articles dealing with the methodology associated with the design and analysis of this type of study have yet been published in Italian. The aim of this article, therefore, is to provide methodological support to healthcare researchers who are planning a CRT, through a description of the methodology used in the Raffaello project. This project is in the start-off phase in the Marche and Abruzzo regions of Italy and represents an excellent case study, it being a CRT aimed at evaluating the efficacy of a Disease Management model in the general population (with general practitioners therefore, being the cluster of randomization).


Next generation sequencing characterizes HLA diversity in a registry population from the Netherlands.
Next generation DNA sequencing is used to determine the HLA-A, -B, -C, -DRB1, -DRB3/4/5, and -DQB1 assignments of 1009 unrelated volunteers for the unrelated donor registry in The Netherlands. The analysis characterizes all HLA exons and introns for class I alleles; at least exons 2 to 3 for HLA-DRB1; and exons 2 to 6 for HLA-DQB1. Of the distinct alleles present, there are 229 class I and 71 class II; 36 of these alleles are novel. The majority (approximately 98%) of the cumulative allele frequency at each locus is contributed by alleles that appear three or more times. Alleles encoding protein variation outside of the antigen recognition domains are 0.6% of the class I assignments and 5.3% of the class II assignments.


Comparison of post-creation procedures and costs between surgical and an endovascular approach to arteriovenous fistula creation.
Due to early and late failures that may occur with surgically created hemodialysis arteriovenous fistulas (SAVF), post-creation procedures are commonly required to facilitate AVF maturation and maintain patency. This study compared AVF post-creation procedures and their associated costs in patients with SAVF to patients with a new endovascularly created AVF (endoAVF). A 5% random sample from Medicare Standard Analytical Files was abstracted to determine post-creation procedures and associated costs for SAVF created from 2011 to 2013. Medicare enrollment during the 6 months prior to and after the AVF creation was required. Patients' follow-up inpatient, outpatient, and physician claims were used to identify post-creation procedures and to estimate average procedure costs. Comparative procedural information on endoAVF was obtained from the Novel Endovascular Access Trial (NEAT). Of 3764 Medicare SAVF patients, 60 successfully matched to endoAVF patients using 1:1 propensity score matching of baseline demographic and clinical characteristics. The total post-creation procedural event rate within 1 year was lower for endoAVF patients (0.59 per patient-year) compared to the matched SAVF cohort (3.43 per patient-year; p<0.05). In the endoAVF cohort, event rates of angioplasty, thrombectomy, revision, catheter placement, subsequent arteriovenous graft (AVG), new SAVF, and vascular access-related infection were all significantly lower than in the SAVF cohort. The average first year cost per patient-year associated with post-creation procedures was estimated at US$11,240 USD lower for endoAVF than for SAVF. Compared to patients with SAVF, patients with endoAVF required fewer post-creation procedures and had lower associated mean costs within the first year.


How long should suction drains stay in after breast surgery with axillary dissection?
Daily suction drainage volumes were recorded for 63 patients after wide local excision of a breast carcinoma with axillary dissection (n = 37) or mastectomy with axillary dissection (n = 26). Suction drains were removed at the discretion of the clinical ward staff after a median of 4 days (range 1-7 days). In all, 32 patients (51%) later developed seromas requiring needle aspiration. Minor wound infection rate was not significantly higher in patients who developed seromas than those who did not (5 vs 2). Seroma formation was associated with a larger total suction drain volume (mean 480 ml (range 28-1150 ml) vs 240 ml (range 10-635 ml); P = 0.0001). The median yield of axillary lymph nodes was significantly greater in those who developed seromas (11 (range 4-20) vs 8 (range 1-19); P = 0.002). There was no difference in the volume drained in the 24 h preceding drain removal (mean 60 ml (range 0-150 ml) vs 50 ml (range 0-290 ml); NS). Keeping drains in situ longer did not protect against seroma formation. By 48 h, 74% of the total volume drained by each drain had been collected. Seroma formation after breast surgery with axillary dissection is an inconvenience for a high proportion of patients. This complication does not seem to be reduced by prolonged suction drainage of the wound, which in itself delays patient discharge and causes further inconvenience.


Use of metformin and survival of diabetic women with breast cancer.
This study was set out to determine whether metformin use influences survival in breast cancer patients treated with antidiabetic drugs as compared to non-users. We used data from the Danish national registries (1996-2008) to identify adult female patients diagnosed with breast cancer who were prescribed antidiabetic medication. We performed multivariate Coxproportional hazard regression to assess all-cause and breast cancer-specific mortality risks associated with metformin exposure. In a secondary analysis, we stratified use of metformin according to the cumulative number of prescriptions. Of the 1058 breast cancer patients 349 died during follow-up, with breast cancer listed as the primary cause of death for 152 cases. Compared to non-use, current metformin treatment was associated with a significant reduction in overall mortality (adjusted HR 0.74, 95% CI, 0.58-0.96). For breast cancer-specific mortality, a non-significant risk reduction (adjusted HR 0.88, 95% CI, 0.59-1.29) was observed, which became significant after stratification according to cumulative number of prescriptions. An increased risk of both overall and breast cancer-specific mortality was observed in the first 12 months after discontinuation of metformin. We observed a nonsignificant reduction in breast cancer-specific mortality associated with metformin exposure among breast cancer patients treated with antidiabetic drugs. However, our findings suggest that long-term metformin use may have a beneficial effect on survival in patients with breast cancer. Further confirmation of these findings is needed.


Bayesian online learning of the hazard rate in change-point problems.
Change-point models are generative models of time-varying data in which the underlying generative parameters undergo discontinuous changes at different points in time known as change points. Change-points often represent important events in the underlying processes, like a change in brain state reflected in EEG data or a change in the value of a company reflected in its stock price. However, change-points can be difficult to identify in noisy data streams. Previous attempts to identify change-points online using Bayesian inference relied on specifying in advance the rate at which they occur, called the hazard rate (h). This approach leads to predictions that can depend strongly on the choice of h and is unable to deal optimally with systems in which h is not constant in time. In this letter, we overcome these limitations by developing a hierarchical extension to earlier models. This approach allows h itself to be inferred from the data, which in turn helps to identify when change-points occur. We show that our approach can effectively identify change-points in both toy and real data sets with complex hazard rates and how it can be used as an ideal-observer model for human and animal behavior when faced with rapidly changing inputs.


Measuring local-directional resolution and local anisotropy in cryo-EM maps.
The introduction of local resolution has enormously helped the understanding of cryo-EM maps. Still, for any given pixel it is a global, aggregated value, that makes impossible the individual analysis of the contribution of the different projection directions. We introduce MonoDir, a fully automatic, parameter-free method that, starting only from the final cryo-EM map, decomposes local resolution into the different projection directions, providing a detailed level of analysis of the final map. Many applications of directional local resolution are possible, and we concentrate here on map quality and validation.


Seascape genomics as a new tool to empower coral reef conservation strategies: An example on north-western Pacific Acropora digitifera.
Coral reefs are suffering a major decline due to the environmental constraints imposed by climate change. Over the last 20 years, three major coral bleaching events occurred in concomitance with anomalous heatwaves, provoking a severe loss of coral cover worldwide. The conservation strategies for preserving reefs, as they are implemented now, cannot cope with global climatic shifts. Consequently, researchers are advocating for preservation networks to be set-up to reinforce coral adaptive potential. However, the main obstacle to this implementation is that studies on coral adaption are usually hard to generalize at the scale of a reef system. Here, we study the relationships between genotype frequencies and environmental characteristics of the sea (seascape genomics), in combination with connectivity analysis, to investigate the adaptive potential of a flagship coral species of the Ryukyu Archipelago (Japan). By associating genotype frequencies with descriptors of historical environmental conditions, we discovered six genomic regions hosting polymorphisms that might promote resistance against heat stress. Remarkably, annotations of genes in these regions were consistent with molecular roles associated with heat responses. Furthermore, we combined information on genetic and spatial distances between reefs to predict connectivity at a regional scale. The combination of these results portrayed the adaptive potential of this population: we were able to identify reefs carrying potential heat stress adapted genotypes and to understand how they disperse to neighbouring reefs. This information was summarized by objective, quantifiable and mappable indices covering the whole region, which can be extremely useful for future prioritization of reefs in conservation planning. This framework is transferable to any coral species on any reef system and therefore represents a valuable tool for empowering preservation efforts dedicated to the protection of coral reefs in warming oceans.


Survival analysis, long-term outcomes, and percentage of recovery up to 8 years post-infection among the Houston West Nile virus cohort.
In 2012, we witnessed a resurgence of West Nile virus (WNV) in the United States, with the largest outbreak of human cases reported since 2003. WNV is now endemic and will continue to produce epidemics over time, therefore defining the long-term consequences of WNV infection is critical. Over a period of eight years, we prospectively followed a cohort of 157 WNV-infected subjects in the Houston metropolitan area to observe recovery over time and define the long-term clinical outcomes. We used survival analysis techniques to determine percentage of recovery over time and the effects of demographic and co-morbid conditions on recovery. We found that 40% of study participants continued to experience symptoms related to their WNV infection up to 8 years later. Having a clinical presentation of encephalitis and being over age 50 were significantly associated with prolonged or poor recovery over time. Since the health and economic impact as a result of prolonged recovery, continued morbidity, and related disability is likely substantial in those infected with WNV, future research should be aimed at developing effective vaccines to prevent illness and novel therapeutics to minimize morbidity, mortality, and long-term complications from infection.


Effect of flow-resistive inspiratory loading on pulmonary and respiratory muscle function in sub-elite swimmers.
The aim of this study was to evaluate the effects of a 12-week swim training and inspiratory muscle training program on respiratory muscle and pulmonary function in competitively trained sub-elite swimmers. A double-blind, parallel-group experimental design was employed to compare the effects of swim training alone, swim training with sham-inspiratory muscle training, and swim training with true inspiratory muscle training. Twenty-four competitively trained sub-elite swimmers combined swim training with either flow-resistive inspiratory muscle training set at 80% sustained maximal inspiratory pressure with progressively increased work-rest ratios until task failure for 3 days/week (swim training with inspiratory muscle training, N.=8), or swim training with sham-inspiratory muscle training (N.=8), or acted as controls (swim training only, N.=8). Measures of pulmonary and respiratory muscle function were assessed at the beginning and end of the 12-week study period. At baseline, there were no significant differences (P>0.05) in respiratory muscle and pulmonary function between groups. Following the 12-week training period, the swim training with inspiratory muscle training group demonstrated improvements in maximal inspiratory pressure, sustained maximal inspiratory pressure, maximal inspiratory muscle power output, inspiratory muscle work capacity, inspiratory time of contraction, time to fatigue, maximal voluntary ventilation in 12 seconds, and forced inspiratory volume in 1-second (P<0.05). No improvements in pulmonary or respiratory muscle function were observed in the swim training only or swim training with sham-inspiratory muscle training groups (P>0.05). Inspiratory muscle training in conjunction with swim training improves respiratory muscle function in sub-elite swimmers when compared to swim training only.


The Kardashian index: a measure of discrepant social media profile for scientists.
In the era of social media there are now many different ways that a scientist can build their public profile; the publication of high-quality scientific papers being just one. While social media is a valuable tool for outreach and the sharing of ideas, there is a danger that this form of communication is gaining too high a value and that we are losing sight of key metrics of scientific value, such as citation indices. To help quantify this, I propose the 'Kardashian Index', a measure of discrepancy between a scientist's social media profile and publication record based on the direct comparison of numbers of citations and Twitter followers.


Lattice defects in microtubules: protofilament numbers vary within individual microtubules.
We have used cryo-electron microscopy of vitrified specimens to study microtubules assembled both from three cycle purified tubulin (3x-tubulin) and in cell free extracts of Xenopus eggs. In vitro assembled 3x-tubulin samples have a majority of microtubules with 14 protofilaments whereas in cell extracts most microtubules have 13 protofilaments. Microtubule polymorphism was observed in both cases. The number of protofilaments can change abruptly along individual microtubules usually by single increments but double increments also occur. For 3x-tubulin, increasing the magnesium concentration decreases the proportion of 14 protofilament microtubules and decreases the average separation between transitions in these microtubules. Protofilament discontinuities may correspond to dislocation-like defects in the microtubule surface lattice.


Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease.
Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.


Simultaneous sensing and imaging of individual biomolecular complexes enabled by modular DNA-protein coupling.
Many proteins form dynamic complexes with DNA, RNA, and other proteins, which often involves protein conformational changes that are key to function. Yet, methods to probe these critical dynamics are scarce. Here we combine optical tweezers with fluorescence imaging to simultaneously monitor the conformation of individual proteins and their binding to partner proteins. Central is a protein-DNA coupling strategy, which uses exonuclease digestion and partial re-synthesis to generate DNA overhangs of different lengths, and ligation to oligo-labeled proteins. It provides up to 40 times higher coupling yields than existing protocols and enables new fluorescence-tweezers assays, which require particularly long and strong DNA handles. We demonstrate the approach by detecting the emission of a tethered fluorescent protein and of a molecular chaperone (trigger factor) complexed with its client. We conjecture that our strategy will be an important tool to study conformational dynamics within larger biomolecular complexes.


Multispectral Imaging Approach to the Diagnosis of a CD20+ Cutaneous T-cell Lymphoproliferative Disorder: A Case Report.
Expression of the pan B-cell marker CD20 by T-cell lymphoproliferative disorders is exceedingly rare. We present a 52-year-old man with a unilesional cutaneous CD20 T-cell lymphoproliferative disorder. Multispectral imaging analysis of CD3-CD20 double-stained lesional tissue sections allowed (1) the visualization of double-positive T lymphocytes in situ with sensitivity superior to that of conventional immunohistochemistry and (2) the quantitative assessment of marker coexpression. Here, 23% of CD3 signals in the patient's lesion were also CD20, whereas 38% of CD20 signals were also CD3. In contrast, both parameters were below 1% in the tonsil control. Overall, the percentage of double-positive cells in lesional skin was 35%, although only 0.4% of such cells were detected in the tonsil. This is the first demonstration of aberrant CD20 expression by skin-infiltrating T cells using multispectral imaging.


Usefulness and limitations of thallium-201 myocardial scintigraphy in delineating location and size of prior myocardial infarction.
In order to evaluate the usefulness of thallium-201 (201TI) myocardial scintigraphy in delineating the location and size of prior myocardial infarction, 32 patients were evaluated at a mean of 7 +/- 2 months after infarction with a 12-lead ECG, resting 201TI myocardial scintigram, biplane left ventriculogram and coronary angiograms. From the left ventriculogram, asynergy was quantified as percent abnormally contracting segment (% ACS), the percent of end-diastolic circumference which was either akinetic or dyskinetic. Using a computerized planimetry system, we expressed 201TI perfusion defects as a percentage of total potential thallium uptake. Of 21 patients with ECG evidence of prior transmural infarction, a 201TI defect was present in 20 (95%), and angiographic asynergy was present in all 21 (100%). The site of prior infarction by ECG agreed with the 201TI defect location in 24 of 32 patients (75%) and with site of angiographic asynergy in 23 of 32 patients (72%). Scintigraphic defects were present in only four of 10 patients (40%) with ACS less than or equal to 6%, but scintigraphic defects were found in 20 to 22 patients (91%) with ACS greater than 6% (p less than 0.01). Thallium defect size correlated marginally with angiographic left ventricular ejection fraction (r = -0.60) but correlated closely with angiographic % ACS (r = 0.80). Thallium defect size was similar among patients with one-, two-, or three-vessel coronary artery disease (greater than or equal to 70% stenosis), but thallium defect size was larger in patients with electrocardiographic evidence of transmural infarction (p less than 0.01) or pulmonary capillary wedge pressure greater than 12 mm Hg (p less than 0.001). Thus, resting 201TI myocardial scingigraphy is useful in localizing and quantifying the extent of prior myocardial infarction, but is insensitive to small infarcts (ACS less than 6%).


Tyrosine kinase signaling and type III effectors orchestrating Shigella invasion.
Upon epithelial cell contact, Shigella type III effectors activate complex signaling pathways that induce localized membrane ruffling, resulting in Shigella invasion. Bacterial induced membrane ruffles require a timely coordination of cytoskeletal processes, including actin polymerization, filament reorganization and depolymerization, orchestrated by Rho GTPases and tyrosine kinases. An emerging concept is that multiple Shigella effectors act in synergy to promote actin polymerization in membrane extensions at the site of bacterial entry. Recent advances point to the role of Abl/Arg and Src tyrosine kinases as key regulators of bacterial induced cytoskeletal dynamics.


"Denervation" of autonomous nervous system in idiopathic pulmonary arterial hypertension by low-dose radiation: a case report with an unexpected outcome.
Vasointestinal peptide metabolism plays a key physiological role in multimodular levels of vasodilatory, smooth muscle cell proliferative, parenchymal, and inflammatory lung reactions. In animal studies, vasointestinal peptide relaxes isolated pulmonary arterial segments from several mammalian species in vitro and neutralizes the pulmonary vasoconstrictor effect of endothelin. In some animal models, it reduces pulmonary vascular resistance in vivo and in monocrotaline-induced pulmonary hypertension. A 58-year-old woman presented with dyspnea and mild edema of the lower extremities. A bronchoscopy was performed without any suspicious findings suggesting a central tumor or other infiltrative disease. Endobronchial ultrasound revealed enlarged pulmonary arteries containing thrombi, a few enlarged lymph nodes, and enlarged mediastinal tissue anatomy with suspicion for mediastinal infiltration of a malignant process. We estimated that less than 10% of the peripheral vascular bed of the lung was involved in direct consolidated fibrosis as demonstrated in the left upper lobe apex. Further, direct involvement of fibrosis around the main stems of the pulmonary arteries was assumed to be low from positron emission tomography and magnetic resonance imaging scans. Assuming a positive influence of low-dose radiation, it was not expected that this could have reduced pulmonary vascular resistance by over two thirds of the initial result. However; it was noted that this patient had idiopathic pulmonary arterial hypertension mixed with "acute" (mediastinal) fibrosis which could have contributed to the unexpected success of reduction of pulmonary vascular resistance. To the best of our knowledge, this is the first report of successful treatment of idiopathic pulmonary arterial hypertension, probably as a result of low-dose radiation to the pulmonary arterial main stems. The patient continues to have no specific complaints concerning her idiopathic pulmonary arterial hypertension.


Tumor susceptibility and apoptosis defect in a mouse strain expressing a human p53 transgene.
Activation of apoptosis is believed to be critical for the role of p53 as a tumor suppressor. Here, we report a new mouse strain carrying a human p53 transgene in the mouse p53-null background. Expression of human p53 in these mice was comparable with wild-type murine p53; however, transactivation, induction of apoptosis, and G(1)-S checkpoint, but not transrepression or regulation of a centrosomal checkpoint, were deregulated. Although multiple functions of p53 were abrogated, mice carrying the human p53 transgene did not show early onset of tumors as typically seen for p53-null mice. In contrast, human p53 in the p53-null background did not prevent accelerated tumor development after genotoxic or oncogenic stress. Such behavior of human p53 expressed at physiologic levels in transgenic cells could be explained by unexpectedly high binding with Mdm2. By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells. Our findings indicate that the interaction between p53 and Mdm2 controls p53 transcriptional activity in homeostatic tissues and regulates DNA damage- and oncogene-induced, but not spontaneous, tumorigenesis.


Role of complement in C-reactive-protein-mediated protection of mice from Streptococcus pneumoniae.
Expression of a human C-reactive protein (CRP) transgene has been shown to protect mice from lethal Streptococcus pneumoniae infection. In the present study, we used cobra venom factor-induced decomplementation to investigate the role of complement in this CRP-mediated protection. An intact complement system significantly reduced pneumococcal bacteremia at 24 h postinfection and extended median survival time of both CRP-transgenic and nontransgenic mice. However, mortality was significantly lowered only for CRP transgenic mice. The transgene significantly reduced bacteremia for both normocomplementemic and decomplemented mice, but it resulted in a significantly longer median survival time and lower mortality only for normocomplementemic mice. These data suggest that in vivo complement and CRP amplify each other's protective capacity, particularly during the early course of infection.


Frequency of diarrhoea as a predictor of elevated blood pressure in children.
Diarrhoeal illness is a major public health problem for children worldwide, particularly among developing countries, and is a proxy condition for severe dehydration. It has been hypothesized that severe dehydration in the first 6 months of life could be associated with increased blood pressure later in life. This study aimed to explore whether frequency of diarrhoea is associated with elevated blood pressure in children in a setting with a high incidence of diarrhoeal disease. The present study is a cross-sectional study of blood pressure among children from a longitudinal child diarrhoeal disease cohort in Lima, Peru. From 2001 to 2006, daily diarrhoeal surveillance was made. Children were revisited in 2006 and blood pressure was measured. Diarrhoeal exposures were evaluated in terms of total number of diarrhoea days, number of episodes of diarrhoea, persistent diarrhoeal episodes and by the quartiles of daily incidence and episode incidence of diarrhoea. The overall incidence of diarrhoeal episodes at age under 1 year was 4.35 (95% confidence interval: 3.79-4.98) and under 5 years was 2.80 (95% confidence interval: 2.69-2.92). No association was observed between the total number of diarrhoeal days, diarrhoeal episodes or diarrhoeal incidence rates with childhood blood pressure. There was weak evidence that hospital admission due to severe dehydration in the first year of life showed a gradient towards an increase in both, systolic and diastolic blood pressure. In the first study to date to examine the association in a setting with a high incidence of diarrhoeal disease, diarrhoeal frequency did not show an association with increased blood pressure. Our observations of elevated levels of blood pressure among those admitted into hospitals in the first year of life are in line with the original hypothesis of dehydration in early infancy and high blood pressure. However, the effect of episodes of severe dehydration on later blood pressure remains uncertain.


Combined use of Rapid Bioassessment Protocols and Sediment Quality Triad to assess stream quality.
Physical, chemical and biological conditions at five stations on a small southeastern stream were evaluated using the Rapid Bioassessment Protocols (RBP) and the Sediment Quality Triad (SQT) to assess potential biological impacts of a municipal wastewater treatment facility (WWTF) on downstream resources. Physical habitat, benthic macroinvertebrates and fish assemblages were impaired at Stations 1 and 2 (upstream of the WWTF), suggesting that the degraded physical habitat was adversely impacting the fish and benthic populations. The SQT also demonstrated that Stations 1 and 2 were degraded, but the factors responsible for the impaired conditions were attributed to the elevated concentrations of polycylclic aromatic hydrocarbons (PAHs) and metals (Mn, Pb) in the sediments. The source of contaminants to the upper reaches of the stream appears to be storm-water runoff from the city center. Increased discharge and stabilized base flow contributed by the WWTF appeared to benefit the physically-altered stream system. Although the two assessment procedures demonstrated biological impairment at the upstream stations, the environmental factors identified as being responsible for the impairment were different: the RBP provided insight into contributions associated with the physical habitat and the SQT contributed information on contaminants and sediment quality. Both procedures are important in the identification of physical and chemical factors responsible for environmental impairment and together they provide information critical to the development of appropriate management options for mitigation.