Predicting Cancer Cell Line Dependencies From the Protein Expression Data of Reverse-Phase Protein Arrays.
Predicting cancer dependencies from molecular data can help stratify patients and identify novel therapeutic targets. Recently available data on large-scale cancer cell line dependency allow a systematic assessment of the predictive power of diverse molecular features; however, the protein expression data have not been rigorously evaluated. By using the protein expression data generated by reverse-phase protein arrays, we aimed to assess their predictive power in identifying cancer dependencies and to develop a related analytic tool for community use. By using a machine learning schema, we conducted an analysis of feature importance based on cancer dependency and multiomic data from the DepMap and Cancer Cell Line Encyclopedia projects. We assessed the consistency of cancer dependency data between CRISPR/Cas9 and short hairpin RNA-mediated perturbation platforms. For a fair comparison, we focused on a set of genes with robust dependency data and four available expression-related features (copy number alteration, DNA methylation, messenger RNA expression, and protein expression) and performed the same-gene predictions of the cancer dependency using different molecular features. For the genes surveyed, we observed that the protein expression data contained substantial predictive power for cancer dependencies, and they were the best predictive feature for the CRISPR/Cas9-based dependency data. We also developed a user-friendly protein-dependency analytic module and integrated it with The Cancer Proteome Atlas; this module allows researchers to explore and analyze our results intuitively. This study provides a systematic assessment for predicting cancer dependencies of cell lines from different expression-related features of a gene. Our results suggest that protein expression data are a highly valuable information resource for understanding tumor vulnerabilities and identifying therapeutic opportunities.


Synthesis, characterization, antimicrobial, and pharmacological evaluation of some 2, 5-disubstituted sulfonyl amino 1,3,4-oxadiazole and 2-amino-disubstituted 1,3,4-thiadiazole derivatives.
The presence of heterocyclic structures in diverse types of compounds, this is strongly indicative of the profound effect like structure exerts on physiologic activity, and recognition of this is abundantly reflected in efforts to find useful synthetic drugs. The search for better pharmacological active drug and the importance of disubstituted 1,3,4-oxadiazole and 1,3,4-thiadiazole as active pharmacophores, prompted us to design, synthesize, characterize, and evaluate a series of differently substituted sulfonyl amino 1,3,4-oxadiazole and 1,3,4-thiadiazole for their potential antimicrobial, analgesic and antiinflammatory activity, respectively. New sulfonyl amino 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives were synthesized by intramolecular cyclization of thiosemicarbazide in alkaline medium. Reactions were carried out by the reaction between aromatic carbonyl halide and thiosemicarbazide.


Serum des-gamma-carboxyprothrombin in patients with pancreatic head adenocarcinoma.
The total des-gamma-carboxyprothrombin (DCP) produced in pancreatic adenocarcinoma and the correlation between the tissue DCP and serum DCP levels has been examined. Fifty patients with resectable pancreatic head cancer were examined regarding both the tissue and serum levels of DCP. The mean tissue DCP in the cancer tissue, non-cancer tissue, the serum levels in patients, and the serum levels in controls was 190.500 mAU/ml mg protein, 32.000 mAU/ml mg protein, and 46.000 mAU, and 10.000 mAU, respectively. The elevation of tissue and serum levels of DCP in pancreatic adenocarcinoma patients is a very useful marker for pancreatic adnocarcinoma and should be used without any other tumor marker (Tab. 2, Ref. 15).


Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice.
Infused C-type natriuretic peptide (CNP) was recently found to play a cardioprotective role in preventing myocardial ischaemia/reperfusion (I/R) injury and improving cardiac remodelling after myocardial infarction (MI) in rats. Our study aimed to investigate the effect of cardiomyocyte-specific CNP over-expression on I/R injury and MI in transgenic mice. We generated transgenic (TG) mice over-expressing CNP in cardiomyocytes. Elevated CNP expression on RNA and protein levels was demonstrated by RNase-protection assay and radioimmunoassay. Male TG mice and age-matched wild-type (WT) littermates were subjected to 1-hour global myocardial ischaemia and 23 h of reperfusion or permanent ligation of the coronary artery for 3 weeks. Infarct size did not differ between the WT and TG groups in mice subjected to I/R. In mice that underwent permanent ligation of coronary arteries, both left and right ventricular hypertrophy were prevented by CNP over-expression 3 weeks post-MI. Histological analysis revealed less necrosis, muscular degeneration and inflammation in infarcted TG mice. Impairment of cardiac function was less pronounced in transgenic animals than in the wild-type controls. Over-expression of CNP in cardiomyocytes does not affect I/R-induced infarct size but prevents cardiac hypertrophy induced by MI. Therefore, CNP may represent a potent therapeutic target for the treatment of patients with cardiac hypertrophy induced by myocardial infarction or other aetiology.


Determination of acid surface pH in vivo in rat proximal jejunum.
Surface pH of rat intestine was measured in vivo in exteriorised loops using pH-electrodes. Surface pH was approximately 6.1 in Krebs-phosphate buffer in proximal jejunum and was significantly more acid (p less than 0.01) than the bulk medium pH of 7.2. Values for the midgut were approximately 6.5, yet the distal ileum gave values of 7.3, which was marginally more alkaline than the buffer. These results agree with the known acidification phenomenon in the jejunum and the alkalinisation process in the ileum. No difference in surface pH was detected when bicarbonate buffer was used, nor when glucose was included in the buffer. The acid surface pH was almost completely inhibited when jejunal loops were made anoxic by completely occluding the blood supply, showing that the low surface pH is not itself a consequence of preparative anoxia. If glucose was included in the buffer, allowing glucose access from the luminal surface, surface pH was not significantly altered after occlusion. This indicates that previously reported in vitro results in the presence of glucose are similar to the present in vivo findings. The present experiments confirm the existence in vivo of the 'acid-microclimate' proposed to alter the absorption profiles of some dissociable drugs.


A serum metabolomics-based profile in low bone mineral density postmenopausal women.
Osteoporosis is characterized as a metabolic disorder of bone tissue, and various metabolic markers are now available to support its diagnosis and evaluate treatment effects. Substances produced as end products of metabolomic activities are the correlated factors to the biological or metabolic status, and thus, metabolites are considered highly sensitive markers of particular pathological states, including osteoporosis. Here we undertook comprehensive serum metabolomics analysis in postmenopausal women with or without low bone mineral density (low BMD vs controls) for the first time using capillary electrophoresis/mass spectrometry. Among the metabolites tested, 57 were detected in sera. Levels of hydroxyproline, Gly-Gly and cystine, differed significantly between groups, with Gly-Gly and cystine significantly lower in the low BMD group and hydroxyproline, a reported marker of osteoporosis, significantly higher. Levels of TRACP5b, a bone resorption marker, were significantly higher in the low BMD group, supporting the study's validity. Taken together, our findings represent novel metabolomic profiling in low BMD in postmenopausal women.


Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway.
Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-γ related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-γR1 and IFN-γR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-γ immunity.


Replication and Extension of the Weight Loss For Life Community-Based Treatment Protocol.
Maintaining weight-loss beyond 6-9 months within behavioral treatments has been problematic. However, a social cognitive theory-driven, community-based curriculum emphasizing the generalization of physical activity-related self-regulation, to eating-related self-regulation (phase 1 treatment; n = 55), demonstrated success at both inducing lost weight over its initial 6 months, and maintaining that loss through month 24. The present replication study contrasted those outcomes with a phase 2 version of the year-long treatment (n = 74) that added a follow-up component during year 2 consisting of 5 brief phone interactions to reinforce self-regulatory skills. Participants were all women with obesity (body mass index 30-40 kg/m2; mean age = 48 years). In phase 2, the mean weight loss of 6.3% during baseline-month 6, and regain of 0.7% through month 24, did not significantly differ from phase 1. However, phase 2 methods were associated with significantly better retention of improvements in self-regulation, fruit/vegetable intake, and physical activity. For phase 2 results, second-year change in fruit/vegetable consumption completely mediated the significant relationship between self-regulation and weight change, and change in physical activity completely mediated the significant relationship between self-regulation and weight change, over the 2-year study. Findings suggest the importance of moderate physical activity and more intensive follow-up focused on self-regulation processes.


RepD-mediated recruitment of PcrA helicase at the Staphylococcus aureus pC221 plasmid replication origin, oriD.
Plasmid encoded replication initiation (Rep) proteins recruit host helicases to plasmid replication origins. Previously, we showed that RepD recruits directionally the PcrA helicase to the pC221 oriD, remains associated with it, and increases its processivity during plasmid unwinding. Here we show that RepD forms a complex extending upstream and downstream of the core oriD. Binding of RepD causes remodelling of a region upstream from the core oriD forming a 'landing pad' for the PcrA. PcrA is recruited by this extended RepD-DNA complex via an interaction with RepD at this upstream site. PcrA appears to have weak affinity for this region even in the absence of RepD. Upon binding of ADPNP (non-hydrolysable analogue of ATP), by PcrA, a conformational rearrangement of the RepD-PcrA-ATP initiation complex confines it strictly within the boundaries of the core oriD. We conclude that RepD-mediated recruitment of PcrA at oriD is a three step process. First, an extended RepD-oriD complex includes a region upstream from the core oriD; second, the PcrA is recruited to this upstream region and thirdly upon ATP-binding PcrA relocates within the core oriD.


Gastritis associated with Epstein-Barr virus infection.
Infectious mononucleosis is a self-limiting clinical syndrome caused by primary Epstein-Barr virus (EBV) infection. EBV-associated gastritis, however, has rarely been documented. We report a case of a 17-year-old woman who presented with fever, sore throat, and epigastric pain. Upper endoscopy revealed diffuse granular mucosae and elevated lesions in the stomach. Histologically, the biopsied mucosa was infiltrated by numerous atypical lymphocytes. From clinical, histopathologic, immunohistochemical, and in situ hybridization analyses, we diagnosed EBV-associated gastritis. Her symptoms spontaneously resolved, and follow-up endoscopy revealed improvement and no atypical lymphocytes. To prevent misdiagnosis and unnecessary treatment, the possibility of EBV-associated gastritis should be considered.


Treatment of severe malaria.
In the treatment of severe Plasmodium falciparum infection antimalarial drugs should, ideally, be given by controlled rate intravenous infusion until the patient is able to swallow tablets. In cases where infection has been acquired in a chloroquine resistant area, and where it has broken through chloroquine prophylaxis or where the geographical origin or species are uncertain, quinine is the treatment of choice. When access to parenteral quinine is likely to be delayed, parenteral quinidine is an effective alternative. A loading dose of quinine is recommended in order to achieve therapeutic plasma concentrations as quickly as possible. In the case of chloroquine sensitive P. falciparum infection, chloroquine, which can be given safely by slow intravenous infusion, may be more rapidly effective and has fewer toxic effects than quinine. There is limited experience with parenteral administration of pyrimethamine sulphonamide combinations such as Fansidar, and resistance to these drugs has developed in South East Asia and elsewhere. Mefloquine and halofantrine cannot be given parenterally. Qinghaosu derivatives are not readily available and have not been adequately tested outside China. Supportive treatment includes the prevention or early detection and treatment of complications, strict attention to fluid balance, provision of adequate nursing for unconscious patients and avoidance of harmful ancillary treatments. Anaemia is inevitable and out of proportion to detectable parasitaemia. Hypotension and shock ('algid malaria') are often attributable to secondary gram-negative septicaemia requiring appropriate antimicrobial therapy and haemodynamic resuscitation. Many patients with severe falciparum malaria are hypovolaemic on admission to hospital and require cautious fluid replacement. Failure to rehydrate these patients may lead to circulatory collapse, lactic acidosis, renal failure and severe hyponatraemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of macrophage migration inhibitory factor and CD74 in the inner ear and middle ear in lipopolysaccharide-induced otitis media.
Significant expression of macrophage migration inhibitory factor and its receptor (CD74) was observed in both the middle ear and inner ear in experimental otitis media in mice. Modulation of macrophage migration inhibitory factor and its signaling pathway might be useful in the management of inner ear inflammation due to otitis media. Inner ear dysfunction secondary to otitis media has been reported. However, the specific mechanisms involved are not clearly understood. The aim of this study is to investigate the expression of macrophage migration inhibitory factor and CD74 in the middle ear and inner ear in lipopolysaccharide-induced otitis media. BALB/c mice received a transtympanic injection of either lipopolysaccharide or phosphate-buffered saline (PBS). The mice were sacrificed 24 h after injection, and temporal bones were processed for polymerase chain reaction (PCR) analysis, histologic examination, and immunohistochemistry. PCR examination revealed that the lipopolysaccharide-injected mice showed a significant up-regulation of macrophage migration inhibitory factor in both the middle ear and inner ear as compared with the PBS-injected control mice. The immunohistochemical study showed positive reactions for macrophage migration inhibitory factor and CD74 in infiltrating inflammatory cells, middle ear mucosa, and inner ear in the lipopolysaccharide-injected mice.


A cross-cultural comparison of nurses' ethical concerns.
The aim of this study was to compare Swedish and Chinese nurses' experiences of ethical dilemmas and workplace distress in order to deepen understanding of the challenges neuroscience nurses encounter in different cultures. Qualitative interviews from two previously performed empirical studies in Sweden and China were the basis of this comparative study. Four common content areas were identified in both studies: ethical dilemmas, workplace distress, quality of nursing and managing distress. The themes formulated within each content area were compared and synthesized into novel constellations by means of aggregated concept analysis. Despite wide differences in the two health care systems, the nurse participants had similar experiences with regard to work stress and a demanding work situation. They were struggling with similar ethical dilemmas, which concerned seriously ill patients and the possibilities of providing good care. This indicates the importance of providing nurses with the tools to influence their own work situation and thereby reducing their work-related stress.


Comparison of Associations of DXA and CT Visceral Adipose Tissue Measures With Insulin Resistance, Lipid Levels, and Inflammatory Markers.
Visceral adipose tissue (VAT) measured by computed tomography (CT) is related to insulin resistance, lipids, and serum inflammatory markers. Our objective was to compare the strength of the associations of VAT measured using dual-energy X-ray absorptiometry (DXA-VAT) and CT (CT-VAT) with insulin resistance, serum lipids, and serum markers of inflammation. For 1117 men aged 65 and older enrolled in the Osteoporotic Fractures in Men Study, the cross-sectional associations of DXA-VAT and CT-VAT with homeostasis model assessment of insulin resistance (homa2ir), C-reactive protein, and high-density lipoprotein (HDL) cholesterol were estimated with regression models and compared using a Hausman test. Adjusted for age and body mass index, DXA-VAT was moderately associated with homa2ir (effect size 0.38, 95% confidence interval [CI]: 0.28-0.47) and modestly associated with HDL cholesterol (DXA effect size -0.29, 95% CI: -0.38 to -0.21). These associations were significantly greater than those for CT-VAT with homa2ir (0.30, 95% CI: 0.24-0.37; p value for effect size difference 0.03) and CT-VAT with HDL cholesterol (-0.22, 95% CI: -0.29 to -0.15; p value for difference 0.005). Neither DXA-VAT nor CT-VAT was associated with C-reactive protein after adjustment for age and body mass index (DXA-VAT effect size 0.14, 95% CI: -0.04 to 0.32; CT-VAT effect size 0.08, 95% CI: -0.08 to 0.25; p value for difference 0.35). DXA-VAT has similar or greater associations with insulin resistance and HDL cholesterol as does CT-VAT in older men, confirming the concurrent validity of DXA-VAT. Investigations of how well DXA measurements of VAT predict incident cardiovascular disease events are warranted.


Electron work function: a novel probe for toughness.
In this study, based on the calculation of surface properties, ideal strengths and responses of electron localization to the deformation, it was demonstrated that the fracture toughness of transition metals can be correlated to their electron work function. Within the range where the electron work function is smaller than 4.6 eV, the fracture toughness increases with the electron work function. However, if the electron work function exceeds 4.6 eV, then the fracture toughness decreases with an increase in electron work function. This evidence indicates that electron work function could be a sensitive parameter for material selection in order to control the fracture toughness.


Manipulating the circadian and sleep cycles to protect against metabolic disease.
Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock, and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g., obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude-enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep, and metabolism will also have far-reaching implications for various chronic human diseases and aging.


Correlation of genetic diversity between hosts and parasites in Entamoeba nuttalli isolates from Tibetan and rhesus macaques in China.
Entamoeba nuttalli infection is prevalent in captive and wild macaques. Recent studies have suggested that genotypes of E. nuttalli isolates are correlated with the geographical distribution of host macaques. Correlation of amoebic genotypes with genetic diversity of host macaques was analyzed in present study. Sixty fresh stool samples were obtained from wild Tibetan macaques living in Mount Huang (HS) of the An-hui Province in China. PCR analysis revealed that the most prevalent Entamoeba species was E. chattoni (E. polecki ST2) (86.7%) followed by E. nuttalli (58.3%) and E. coli (25%). Six E. nuttalli HS isolates were successfully cultured. The tRNA-linked short tandem repeat (STR) loci and serine-rich protein gene of E. nuttalli isolates from four different regions of China (Mount Long-hu, Gui-yang, Mount E-mei, and HS, the former three isolates were obtained in previous studies) were studied and high numbers of polymorphisms were detected. When genetic diversity of different populations of E. nuttalli isolates was compared with geographical distance, an r2 value of 0.919 was assigned by a Mantel test based on the tRNA-STR loci. In host macaques, the mtDNA HVS-I gene was also highly polymorphic in each of the genomes. Multiple regression analysis using E. nuttalli tRNA-STR loci genetic, macaque mtDNA HVS-I gene, and geographic distances showed an r2 value of 0.943, indicating that a higher relevance was demonstrated when geographic and host gene factors were considered. Analysis of genetic factor of host would benefit for better understanding of the evolution of E. nuttalli.


Macrophages Enhance Migration in Inflammatory Breast Cancer Cells via RhoC GTPase Signaling.
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. All IBC patients have lymph node involvement and one-third of patients already have distant metastasis at diagnosis. This propensity for metastasis is a hallmark of IBC distinguishing it from less lethal non-inflammatory breast cancers (nIBC). Genetic profiling studies have been conducted to differentiate IBC from nIBC, but no IBC cancer-cell-specific gene signature has been identified. We hypothesized that a tumor-extrinsic factor, notably tumor-associated macrophages, promotes and contributes to IBC's extreme metastatic phenotype. To this end, we studied the effect of macrophage-conditioned media (MCM) on IBC. We show that two IBC cell lines are hyper-responsive to MCM as compared to normal-like breast and aggressive nIBC cell lines. We further interrogated IBC's hyper-responsiveness to MCM using a microfluidic migration device, which permits individual cell migration path tracing. We found the MCM "primes" the IBC cells' cellular machinery to become extremely migratory in response to a chemoattractant. We determined that interleukins -6, -8, and -10 within the MCM are sufficient to stimulate this enhanced IBC migration effect, and that the known metastatic oncogene, RhoC GTPase, is necessary for the enhanced migration response.


Association of bovine respiratory disease or vaccination with serologic response in dairy heifer calves up to three months of age.
To investigate the association of bovine respiratory disease (BRD) or vaccination with serologic response in calves. 94 Holstein calves. To assess the association between BRD and antibody titers, 38 calves < 3 months old that were treated for BRD were matched with 38 untreated calves. To investigate the effect of vaccination on antibody titers, 24 calves were randomly assigned to be vaccinated against bovine respiratory syncytial virus (BRSV), bovine viral diarrhea virus types 1 and 2, bovine herpesvirus type 1 (BHV1), and parainfluenza virus type 3 at 2 weeks of age (n = 6), 5 weeks of age (6), and both 2 and 5 weeks of age (6) or were assigned to be unvaccinated controls (6). Blood samples were obtained at I, 2, 5, and 12 weeks for determination of serum neutralization antibody titers against the vaccine viruses, bovine coronavirus, and Mannheimia haemolytica. Antibody rates of decay were calculated. Calves with initial antibody titers against BRSV < 1:64 that were treated for BRD had a slower rate of anti-BRSV antibody decay than did similar calves that were not treated for BRD. Calves with high initial antibody titers against BRSV and BHV1 had lower odds of BRD than did calves with low initial antibody titers against those 2 pathogens. Vaccination at 2 or 5 weeks of age had no effect on the rate of antibody decay. Clinical BRD and the serologic response of dairy calves were associated with initial antibody titers against BRSV and BHV1. Serologic or clinical responses to viral exposure may differ in calves with low passive immunity.


Intestinal bacterial communities that produce active estrogen-like compounds enterodiol and enterolactone in humans.
Lignans are dietary diphenolic compounds which require activation by intestinal bacteria to exert possible beneficial health effects. The intestinal ecosystem plays a crucial role in lignan metabolism, but the organisms involved are poorly described. To characterize the bacterial communities responsible for secoisolariciresinol (SECO) activation, i.e., the communities that produce the enterolignans enterodiol (ED) and enterolactone (EL), a study with 24 human subjects was undertaken. SECO activation was detected in all tested fecal samples. The intestinal bacteria involved in ED production were part of the dominant microbiota (6 x 10(8) CFU g(-1)), as revealed by most-probable-number enumerations. Conversely, organisms that catalyzed the formation of EL occurred at a mean concentration of approximately 3 x 10(5) CFU g(-1). Women tended to have higher concentrations of both ED- and EL-producing organisms than men. Significantly larger amounts of EL were produced by fecal dilutions from individuals with moderate to high concentrations of EL-producing bacteria. Two organisms able to demethylate and dehydroxylate SECO were isolated from human feces. Based on 16S rRNA gene sequence analyses, they were named Peptostreptococcus productus SECO-Mt75m3 and Eggerthella lenta SECO-Mt75m2. A new 16S rRNA-targeted oligonucleotide probe specific for P. productus and related species was designed and further used in fluorescent in situ hybridization experiments, along with five additional group-specific probes. Significantly higher proportions of P. productus and related species (P = 0.012), as well as bacteria belonging to the Atopobium group (P = 0.035), were typical of individuals with moderate to high concentrations of EL-producing communities.


Prognostic factors in locally advanced colon cancer treated by extended resection.
The impact of clinical, pathologic, and surgical variables on the postoperative morbidity, mortality, and survival of patients undergoing extended resections of colon carcinoma were evaluated. The medical records of 95 patients who underwent extended resections for colon carcinoma between 1953 and 1996 were reviewed. In all cases, in addition to colectomy, 1 or more organs and/or structures were resected en bloc due to a macroscopically based suspicion of tumor invasion. The clinical, pathologic, and surgical parameters were analyzed. Overall survival rates were analyzed according to the method of Kaplan and Meier. Multivariate analysis was performed using the Cox proportional hazards model. Eighty-six patients were treated by curative surgeries and the remaining by palliative resections. Invasion of the organs and/or adjacent structures and regional lymph nodes was found microscopically in 48 and 31 patients, respectively. The median follow-up without postoperative mortality was 47.7 months. The 5-year overall survival rates was 52.6%. The 5-year overall survival rates for patients undergoing curative and palliative surgeries was 58.3% and 0%, respectively. The mean survival time in the palliative surgery group was 3.1 months. Multivariate analysis showed that Karnofsky performance status was strongly related to the risk of postoperative complications (P = .01), and postoperative deaths were associated with the type of surgery and Karnofsky performance status at the time of admission (P = .001). Some patients with locally advanced colon adenocarcinomas undergoing extended resections have a 5-year overall survival rates of 58.3%. Patients could benefit from palliative-intent procedures, but these measures should cautiously be indicated and avoided in patients with low Karnofsky performance status due to high rates of postoperative mortality and poor survival.


Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial.
The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data. isrctn.org Identifier: ISRCTN54669986.


Effect of artificial carbon dioxide foot bathing on critical limb ischemia (Fontaine IV) in peripheral arterial disease patients.
It has been reported that artificial carbon dioxide (CO(2)) foot bathing improves subcutaneous microcirculation in peripheral arterial disease (PAD) patients. However, the effect for critical limb ischemia (CLI) with ulceration or gangrene (Fontaine stage IV) is not identified. The physiological effects of CO(2) bathing and the outcome of limb salvage in such patients were studied. In 18 healthy volunteers (Study I), the dorsal pedis peripheral blood flow was measured by a laser Doppler flow-meter during CO(2) foot bathing (1000 ppm, 37 degrees C) for 10 min. A Holter electrocardiogram was also recording in the same period. Blood flow and cell volume significantly increased during bathing. Eighty-three CLI limbs (Fontaine IV) in 68 PAD patients (Study II) underwent artificial CO(2) foot bathing (for 10 minutes twice daily >2 months) were followed up >6 months. In Study I, analysis of heart rate variability showed that high frequency amplitude (HFA) considerably increased and the ratio of low frequency amplitude to HFA (LF/HF) noticeably decreased during bathing. In Study II, 69 limbs (83.1%) could be salvaged. Twenty-seven of 28 limbs (96.4%) which have ulcer and gangrene in only one toe, 13/16 limbs (81.2%) in multiple toes and 29/39 limbs (74.4%) in all toes and/or heel respectively were saved. The effect of CO(2) enriched water on the subcutaneous microcirculation might be brought about by peripheral vasodilation reflected by increased parasympathetic and decreased sympathetic activity, and the artificial CO(2) foot bathing is clinically effective on salvage of CLI (Fontaine stage IV) limbs.


The many faces of amnesia.
Results from studies of retrograde amnesia provide much of the evidence for theories of memory consolidation. Retrograde amnesia gradients are often interpreted as revealing the time needed for the formation of long-term memories. The rapid forgetting observed after many amnestic treatments, including protein synthesis inhibitors, and the parallel decay seen in long-term potentiation experiments are presumed to reveal the duration of short-term memory processing. However, there is clear and consistent evidence that the time courses obtained in these amnesia experiments are highly variable within and across experiments and treatments. The evidence is inconsistent with identification of basic temporal properties of memory consolidation. Alternative views include modulation of memory and emphasize the roles that hormones and neurotransmitters have in regulating memory formation. Of related interest, converging lines of evidence suggest that inhibitors of protein synthesis and of other biochemical processes act on modulators of memory formation rather than on mechanisms of memory formation. Based on these findings, memory consolidation and reconsolidation studies might better be identified as memory modulation and "remodulation" studies. Beyond a missing and perhaps unattainable time constant of memory consolidation, some current views of memory consolidation assume that memories, once formed, are generally unmodifiable. It is this perspective that appears to have led to the recent interest in memory reconsolidation. But the view adopted here is that memories are continually malleable, being updated by new experiences and, at the same time, altering the memories of later experiences. Studies of memory remodulation offer promise of understanding the neurobiological bases by which new memories are altered by prior experiences and by which old memories are altered by new experiences.


Trends in various types of surgery for hysterectomy and distribution by patient age, surgeon age, and hospital accreditation: 10-year population-based study in Taiwan.
To estimate the trends in various types of hysterectomy (abdominal, vaginal, laparoscopic, and subtotal) and their distribution according to patient age, surgeon age, and hospital accreditation in Taiwan. Retrospective cohort study (Canadian Task Force classification II-2). Population-based National Health Insurance (NHI) database. Women with NHI in Taiwan undergoing various types of hysterectomy to treat noncancerous lesions. Data for this study were obtained from the Inpatient Expenditures by Admissions files of the NHI research database, released by the NHI program in Taiwan for 1996-2005. A total of 234,939 women who underwent various types of hysterectomy were identified for analysis. The number of hysterectomies performed annually remained stationary during the 10-year study. Total abdominal hysterectomies decreased significantly (77.33% in 1996 vs 45.68% in 2005), laparoscopic hysterectomies increased significantly (5.20% vs 40.40%), vaginal hysterectomies decreased (14.70% vs 8.86%), and subtotal abdominal hysterectomies increased (2.76% vs 5.06%). Laparoscopic hysterectomy was more commonly performed in middle-aged women; vaginal hysterectomy was more common in older women; and subtotal abdominal hysterectomy was more common in younger women. Laparoscopic hysterectomy was performed more commonly in regional hospitals (33.11%), followed by medical centers (30.17%) and local hospitals (17.78%). Laparoscopic hysterectomy was performed more commonly in not-for-profit hospitals (30.25%), followed by private hospitals (29.32%) and government-owned hospitals (25.91%). There has been considerable change in the types of surgery used for hysterectomy in Taiwan over the past 10 years. As a minimally invasive approach, laparoscopic hysterectomy represents a profound change for both patients and surgeons.


Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States.
In Gaucher disease, deficient activity of acid β-glucosidase results in accumulation of its substrates, glucosylceramide and glucosylsphingosine, within the lysosomes of cells primarily in the spleen, liver, bone marrow, and occasionally the lung. The multisystem disease is predominantly characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. Enzyme replacement therapy with recombinant human acid β-glucosidase has been the first-line therapy for Gaucher disease type 1 for more than two decades. Eliglustat, a novel oral substrate reduction therapy, was recently approved in the United States and the European Union as a first-line treatment for adults with Gaucher disease type 1. Eliglustat inhibits glucosylceramide synthase, thereby decreasing production of the substrate glucosylceramide and reducing its accumulation. Although existing recommendations for the care of patients with Gaucher disease remain in effect, unique characteristics of eliglustat require additional investigation and monitoring. A panel of physicians with expertise in Gaucher disease and experience with eliglustat in the clinical trials provide guidance regarding the use of eliglustat, including considerations before starting therapy and monitoring of patients on eliglustat therapy.


The effects on cow performance and calf birth and weaning weight of replacing grass silage with brewers grains in a barley straw diet offered to pregnant beef cows of two different breeds.
The effects on cow and calf performance of replacing grass silage with brewers grains in diets based on barley straw and fed to pregnant beef cows are reported. Using a 2 × 2 factorial arrangement of breed and diet, cows pregnant by artificial insemination (n = 34) of two breeds (cross-bred Limousin, n = 19 and pure-bred Luing, n = 15) were fed diets ad libitum which consisted of either (g/kg dry matter) barley straw (664) and grass silage (325; GS) or barley straw (783) and brewers grains (206, BG) and offered as total mixed rations. From gestation day (GD) 168 until 266, individual daily feed intakes were recorded and cow body weight (BW) and body condition score (BCS) measured weekly. Calving date, calf sex, birth and weaning BW, and calf age at weaning were also recorded. Between GD 168 and 266, cross-bred Limousin cows gained more weight than Luing cows (p < 0.05) and cows offered BG gained more weight than cows offered GS (p < 0.001). Luing cows lost more BCS than cross-bred Limousin cows (p < 0.05), but diet did not affect BCS. There were no differences in dry matter intake as a result of breed or diet. Calf birth BW, however, was greater for cows fed BG than GS (44 vs. 38 kg, SEM 1.0, p < 0.001) with no difference between breeds. At weaning, calves born to BG-fed cows were heavier than those born to GS-fed cows (330 vs. 286 kg, SEM 9.3, p < 0.01). In conclusion, replacement of grass silage with brewers grains improved the performance of beef cows and increased calf birth and weaning BW. Further analysis indicated that the superior performance of cows offered the BG diet was most likely due to increases in protein supply which may have improved both energy and protein supply to the foetus.


Influence of cross-link structure, density and mechanical properties in the mesoscale deformation mechanisms of collagen fibrils.
Collagen is a ubiquitous protein with remarkable mechanical properties. It is highly elastic, shows large fracture strength and enables substantial energy dissipation during deformation. Most of the connective tissue in humans consists of collagen fibrils composed of a staggered array of tropocollagen molecules, which are connected by intermolecular cross-links. In this study, we report a three-dimensional coarse-grained model of collagen and analyze the influence of enzymatic cross-links on the mechanics of collagen fibrils. Two representatives immature and mature cross-links are implemented in the mesoscale model using a bottom-up approach. By varying the number, type and mechanical properties of cross-links in the fibrils and performing tensile test on the models, we systematically investigate the deformation mechanisms of cross-linked collagen fibrils. We find that cross-linked fibrils exhibit a three phase behavior, which agrees closer with experimental results than what was obtained using previous models. The fibril mechanical response is characterized by: (i) an initial elastic deformation corresponding to the collagen molecule uncoiling, (ii) a linear regime dominated by molecule sliding and (iii) the second stiffer elastic regime related to the stretching of the backbone of the tropocollagen molecules until the fibril ruptures. Our results suggest that both cross-link density and type dictate the stiffness of large deformation regime by increasing the number of interconnected molecules while cross-links mechanical properties determine the failure strain and strength of the fibril. These findings reveal that cross-links play an essential role in creating an interconnected fibrillar material of tunable toughness and strength.


Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy.
Child conduct problems (CPs) are a robust predictor of adult mental health; the concurrence of callous-unemotional (CU) traits confers specific risk for psychopathy. Psychopathy may be related to disturbances in the oxytocin (OXT) system. Evidence suggests that epigenetic changes in the OXT receptor gene (OXTR) are associated with lower circulating OXT and social-cognitive difficulties. We tested methylation levels of OXTR in 4- to 16-year-old males who met DSM criteria for a diagnosis of oppositional-defiant or conduct disorder and were stratified by CU traits and age. Measures were DNA methylation levels of six CpG sites in the promoter region of the OXTR gene (where a CpG site is a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its lenth, linked together by phosphate binding), and OXT blood levels. High CU traits were associated with greater methylation of the OXTR gene for two cytosine nucleotide and guanine nucleotide phosphate linked sites and lower circulating OXT in older males. Higher methylation correlated with lower OXT levels. We conclude that greater methylation of OXTR characterizes adolescent males with high levels of CU and CPs, and this methylation is associated with lower circulating OXT and functional impairment in interpersonal empathy. The results add genetic evidence that high CU traits specify a distinct subgroup within CP children, and they suggest models of psychopathy may be informed by further identification of these epigenetic processes and their functional significance.


Experience of damage control trauma laparotomy in a limited resource healthcare setting: A retrospective Cohort Study.
Damage control surgery (DCS) is an established option for managing severely injured trauma patients. However, its role in the management of similar patients in the developing world is debatable. The purpose of this study is to describe characteristics and outcomes of patients undergoing DCS. All trauma patients requiring laparotomies from 1996 to 2011 at a tertiary care hospital in South Asia were reviewed. DCS was defined in a patient who underwent a truncated laparotomy where the fascia was primarily left open, with the intention of physiological optimization in the Intensive Care Unit, followed by definitive surgery. The primary outcome was in-hospital mortality. Multivariate logistic regression was used to determine the independent predictors of mortality after adjustment for potential confounders. Of 258 patients, 47 underwent DCS. 40% patients were transferred from other hospitals. The time between injury and operation was 152 minutes (IQR: 90-330). Intra-operative laboratory parameters revealed a median pH of 7.16 (IQR: 7.10-7.27), median temperature of 34.7 (IQR: 34.0-35.4) and median PT of 15.9 (IQR: 12.4-21.2). 55% of the patients survived to discharge from hospital. Of those who died, 86% died before the first take back operation. Packed red blood cell transfusion and vascular injury were independently associated with mortality. Damage control surgery is feasible in developing countries, with more than 50% survival reported at one hospital. Future research should focus on critical care management. Damage Control trauma laparotomy is feasible in tertiary care hospitals with multidisciplinary trauma teams in lesser-developed countries.


Discrete free-surface millifluidics for rapid capture and analysis of airborne molecules using surface-enhanced Raman spectroscopy.
A lithography-free, low-cost, free-surface millifluidic device is reported using discrete liquid interfaces for capturing and detecting gas-phase analyte molecules at low partial pressures out of a gas flow of time-varying composition. The architecture, based on segmented flow, consists of alternating regions of liquid and gas wherein the liquid regions contain surface-enhanced Raman spectroscopy (SERS)-active silver nanoparticles, while the gas regions contain trace quantities of vapor-phase analyte, thereby controlling and optimizing transport and mixing of the gas-phase analyte with the liquid phase. Once absorbed in the liquid phase, the entrained analyte molecules induce aggregation of the aqueous silver nanoparticles. The resulting aggregates consisting of nanoparticles and adsorbed analyte molecules produce intense SERS spectra that reliably identify the absorbed analyte in real time. The approach can be used to determine the time-variable trace chemical composition of a gas stream with applications in, for example, environmental monitoring and online industrial process monitoring, or as a SERS-based detector following gas chromatographic separation. The operation of the system is demonstrated using 4-aminobenzenethiol vapor at 750 ppb, and the detection response time is <2 min.


Infertility in Australia circa 1980: an historical population perspective on the uptake of fertility treatment by Australian women born in 1946-51.
To estimate the prevalence of lifetime infertility in Australian women born in 1946-51 and examine their uptake of treatment. Participants in the Australian Longitudinal Study on Women's Health born in 1946-51 (n=13,715) completed up to four mailed surveys from 1996 to 2004. The odds of infertility were estimated using logistic regression with adjustment for socio-demographic and reproductive factors. Among participants, 92.1% had been pregnant. For women who had been pregnant (n=12738): 56.5% had at least one birth but no pregnancy loss (miscarriage and/or termination); 39.9% experienced both birth and loss; and 3.6% had a loss only. The lifetime prevalence of infertility was 11.0%. Among women who reported infertility (n=1511), 41.7% used treatment. Women had higher odds of infertility when they had reproductive histories of losses only (OR range 9.0-43.5) or had never been pregnant (OR=15.7, 95%CI 11.8-20.8); and higher odds for treatment: losses only (OR range 2.5-9.8); or never pregnant (1.96, 1.28-3.00). Women who delayed their first birth until aged 30+ years had higher odds of treatment (OR range 3.2-4.3). About one in ten women experienced infertility and almost half used some form of treatment, especially those attempting pregnancy after 1980. Older first time mothers had an increased uptake of treatment as assisted reproductive technologies (ART) developed. This study provided evidence of the early uptake of treatment prior to 1979 when the national register of invasive ART was developed and later uptake prior to 1998 when data on non-invasive ART were first collected.


Accuracy of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) score as an objective assessment tool for predicting return-to-work status after head and neck cancer in male survivors.
The objective of this nationwide study in Taiwan was to predict work participation by using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) score as an objective assessment tool. Data from between July 2012 and July 2017 regarding 1206 male head and neck cancer (HNC) survivors with disability aged < 50 years were obtained from the Taiwan Data Bank of Persons with Disability (TDPD). Demographic data and the WHODAS 2.0 scores were analyzed to compare employment statuses among HNC survivors. The WHODAS 2.0 scores in all the domains were lower in unemployed than in employed HNC survivors (p < 0.001). The receiver operating characteristic (ROC) curve revealed that the summary WHODAS 2.0 score (area under curve > 0.8) was an extremely accurate predictive tool. Binary logistic regression revealed that the severity levels of impairment and standardized WHODAS 2.0 summary scores less than the cutoff value (27.81) were predictors for the return-to-work (RTW) status of HNC survivors with disability in the working age group. The WHODAS 2.0 score is an objective quantitative assessment tool for evaluating the RTW possibility among these patient groups.


Impulsivity in early psychosis: A complex link with violent behaviour and a target for intervention.
Violent behaviour (VB) occurs in first episode of schizophrenia and can have devastating impact both on victims and patients themselves. A better knowledge of the underlying mechanisms of VB may pave the way to preventive treatments. 1) To explore the nature of the link between impulsivity and VB in early psychosis (EP) patients; 2) To explore the interactions between impulsivity and substance abuse, insight, and positive symptoms, the main dynamic risk factors of VB described to date. Post hoc analysis of data acquired in the frame of a 36-months EP cohort study. A total of 265 EP patients, aged 18 to 35, treated at TIPP (Treatment and early Intervention in Psychosis Program), at the Department of Psychiatry in Lausanne, Switzerland, were included in the study. Logistic regression analyzes were performed as well as mediation analysis and interaction analysis RESULTS: Our data suggest that impulsivity is a predictor of VB when analyzed independently and as part of a multi-factorial model. Impulsivity continues to differentiate violent patients from non-violent ones at the end of the program. In addition, the relationship between impulsivity and VB is not mediated by substance abuse. Finally, the effect of impulsivity on the probability of VB is potentiated by the interaction of different levels of insight and positive symptoms. Early intervention strategies in psychotic disorders should include evaluation of impulsivity considering it is linked to increased risk of VB and may respond to treatment.


Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma.
Poor differentiation and microvascular invasion are indicators of poor outcome after hepatectomy for patients with small hepatocellular carcinoma (HCC). We investigated whether gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging (MRI) could predict these factors before hepatectomy. Between July 2008 and April 2012, 75 patients who underwent hepatectomy for small HCCs (diameter: ≤3cm, tumor number: ≤3) were consecutively enrolled. In gadoxetic acid-enhanced MRI, the signal intensity in the tumor was corrected to that in the paraspinous muscles, and the relative enhancement was calculated. In diffusion-weighted imaging, we measured the apparent diffusion coefficient (ADC). We then investigated the correlations between relative enhancement or ADC and histological grade, microvascular invasion and recurrence-free survival. Poorly differentiated HCCs showed significantly lower ADC than well-differentiated and moderately differentiated HCCs. There was no significant difference in the hepatobiliary phase. Only ADC was an independent predictor of microvascular invasion, and the best cut-off point of its prediction was 1.175×10(-3)mm(2)/s. Additionally, the recurrence-free survival was significantly shorter in low-ADC group than in high-ADC group. ADC is useful for predicting poorly differentiated HCCs and microvascular invasion, and low ADC is associated with increased recurrence risk for small HCCs after hepatectomy.


Design and assembly of pH-sensitive lipidic cubic phase matrices for drug release.
Bicontinuous lipidic cubic phases (LCPs) exhibit a combination of material properties that make them highly interesting for various biomaterial applications: they are nontoxic, biodegradable, optically transparent, thermodynamically stable in excess water, and can incorporate active molecules of virtually any polarity. Here we present a molecular system comprising host lipid, water, and designed lipidic additive, which form a structured, pH-sensitive lipidic matrix for hydrophilic as well as hydrophobic drug incorporation and release. The model drug doxorubicin (Dox) was loaded into the LCP. Tunable interactions with the lipidic matrix led to the observed pH-dependent drug release from the phase. The rate of Dox release from the cubic phase at pH 7.4 was low but increased significantly at more acidic pH. A small amount of a tailored diacidic lipid (lipid 1) added to the monoolein LCP modified the release rate of the drug. Phase identity and structural parameters of pure and doped mesophases were characterized by small-angle X-ray scattering (SAXS), and release profiles from the matrix were monitored electrochemically. Analysis of the release kinetics revealed that the total amount of drug released from the LCP matrix is linearly dependent on the square root of time, implying that the release mechanism proceeds according to the Higuchi model.


Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma.
Hemangioma is the most common soft-tissue tumor of infancy. Despite the frequency of these vascular tumors, the origin of hemangioma-endothelial cells is unknown. Circulating endothelial progenitor cells (EPCs) have recently been identified as vascular stem cells with the capacity to contribute to postnatal vascular development. We have attempted to determine whether circulating EPCs are increased in hemangioma patients and thereby provide insight into the role of EPCs in hemangioma growth. Peripheral blood mononuclear cells (PBMCs) were isolated from hemangioma patients undergoing surgical resection (N = 5) and from age-matched controls (N = 5) undergoing strabismus correction surgery. PBMCs were stained with fluorescent-labeled antibodies for AC133, CD34, and VEGFR2/KDR. Fluorescent-labeled isotype antibodies served as negative controls. Histologic sections of surgical specimens were stained with the specific hemangioma markers Glut1, CD32, and merosin, to confirm the diagnosis of common hemangioma of infancy. EPCs harvested from healthy adult volunteers were stained with Glut1, CD32, and merosin, to assess whether cultured EPCs express known hemangioma markers. Hemangioma patients had a 15-fold increase in the number of circulating CD34 AC133 dual-staining cells relative to controls (0.78+/-0.14% vs.0.052+/-0.017%, respectively). Similarly, the number of PBMCs that stained positively for both CD34 and KDR was also increased in hemangioma patients (0.49+/-0.074% vs. 0.19+/-0.041% in controls). Cultured EPCs stained positively for the known hemangioma markers Glut1, CD32, merosin. This is the first study to suggest a role for EPCs in the pathogenesis of hemangioma. Our results imply that increased levels of circulating EPCs may contribute to the formation of this vascular tumor.


Expression and regulation of estrogen receptors in mesangial cells: influence on matrix metalloproteinase-9.
Diabetic glomerulosclerosis is characterized by the accumulation of extracellular matrix (ECM) in the mesangium. Estrogens seem to retard whereas estrogen deficiency seems to accelerate progressive glomerulosclerosis. Thus, mesangial cells (MC) may be a target for estrogens. Estrogen action is mediated via estrogen receptor (ER) subtypes ERalpha and ERbeta. Both ER subtypes were expressed in human and mouse MC. Using an estrogen-responsive reporter construct in transfection assays, it also was demonstrated that the nuclear ER were transcriptionally active. In the presence of 17beta-estradiol (E2; 10(-10) to 10(-8) M), there was a progressive increase in the mRNA levels of both ERalpha (approximately 1.8-fold and approximately 2.7-fold after 24 and 72 h, respectively) and ERbeta (approximately 1.3-fold and approximately 2.2-fold after 24 and 72 h, respectively). ERalpha protein levels increased approximately 2.5-fold after 24 h (10(-10) M, E2) and up to approximately 5.4-fold after 72 h (10(-9) M, E2). ERbeta protein levels increased approximately 2.1-fold in the presence of E(2) (10(-9) M) after 24 h. Thus, estrogens positively regulate the expression of the ER subtypes, thereby maintaining or increasing MC responsiveness to estrogens. Because diabetic glomerulosclerosis may be due partly to a decrease in ECM degradation, the effects of estrogens on matrix metalloproteinases (MMP) were studied. It was found that E2 (10(-10) to 10(-8) M) increased both MMP-9 mRNA and MMP-9 activity in MC. This may be an important mechanism by which estrogens influence ECM turnover and protect against progression of diabetic glomerulosclerosis.


Influence of magnetic fields on magneto-aerotaxis.
The response of cells to changes in their physico-chemical micro-environment is essential to their survival. For example, bacterial magnetotaxis uses the Earth's magnetic field together with chemical sensing to help microorganisms move towards favoured habitats. The studies of such complex responses are lacking a method that permits the simultaneous mapping of the chemical environment and the response of the organisms, and the ability to generate a controlled physiological magnetic field. We have thus developed a multi-modal microscopy platform that fulfils these requirements. Using simultaneous fluorescence and high-speed imaging in conjunction with diffusion and aerotactic models, we characterized the magneto-aerotaxis of Magnetospirillum gryphiswaldense. We assessed the influence of the magnetic field (orientation; strength) on the formation and the dynamic of a micro-aerotactic band (size, dynamic, position). As previously described by models of magnetotaxis, the application of a magnetic field pointing towards the anoxic zone of an oxygen gradient results in an enhanced aerotaxis even down to Earth's magnetic field strength. We found that neither a ten-fold increase of the field strength nor a tilt of 45° resulted in a significant change of the aerotactic efficiency. However, when the field strength is zeroed or when the field angle is tilted to 90°, the magneto-aerotaxis efficiency is drastically reduced. The classical model of magneto-aerotaxis assumes a response proportional to the cosine of the angle difference between the directions of the oxygen gradient and that of the magnetic field. Our experimental evidence however shows that this behaviour is more complex than assumed in this model, thus opening up new avenues for research.


Protease inhibitors targeting coronavirus and filovirus entry.
In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics.


Analysis of kalirin-7 knockout mice reveals different effects in female mice.
Estradiol treatment of ovariectomized rodents is known to affect the morphology of dendritic spines and produce behavioral and cognitive effects. Kalirin-7 (Kal7), a postsynaptic density (PSD)-localized Rho-guanine nucleotide exchange factor, is important for dendritic spine formation and stability. Male Kal7 knockout [Kal7(KO)] mice exhibit a number of abnormal behavioral and biochemical phenotypes. Given that chronic 17β-estradiol (E2) replacement of ovariectomized rats enhanced Kal7 expression in the hippocampus and primary hippocampal cultures, we assessed the behavioral and biochemical effects of chronic E2 treatment of ovariectomized female wild-type and Kal7(KO) mice. Both intact and ovariectomized Kal7(KO) female mice exhibited decreased anxiety-like behavior compared with the corresponding wild type in the elevated zero maze and were unaffected by E2 treatment. Chronic E2 decreased locomotor activity in the open field and enhanced performance in a passive-avoidance fear conditioning task, which were both unaffected by genotype. Kal7(KO) female mice engaged in significantly more object exploration, both familiar and novel, than did wild-type females. E2 enhanced the acute locomotor response to cocaine, with no significant effect of genotype. Similar to Kal7(KO) males, Kal7(KO) females had decreased levels of N-methyl-d-aspartate receptor 2B in hippocampal PSD fractions with no effect of E2 treatment. The differing behavioral effects of Kal7 ablation in female and male mice may offer insight into the molecular underpinnings of these differences.


An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images.
Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (fMRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie food while brain activity was measured via fMRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype (AA) had increased activity compared with the non-risk (TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.


Alteration of PDGFRβ-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans.
Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt-mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt-mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRα/β was assessed by immunohistochemical staining, the results of which were confirmed by Western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p-PDGFRα-positive tumors were 41.9% (18/43 cases), p-PDGFRβ 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt-mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (P < .05). Phospho-PDGFRβ was well correlated with the phosphorylation of Akt-mTOR pathway proteins in DFSP components of ordinary and FS-DFSPs, but these correlations were weaker in FS components. This study suggested the association of activation of Akt-mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt-mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS.


Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells.
CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by phosphorylation of stress kinases JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Pharmacologic inhibitors of JNK/p38 MAPK conferred protection from P1446A-mediated apoptosis. Treatment with P1446A led to a dramatic induction of NOXA in a JNK-dependent manner, and sensitized CLL cells to ABT-737, a BH3-mimetic. We observed concurrent activation of apoptosis stress-inducing kinase 1 (ASK1) and its interaction with inositol-requiring enzyme 1 (IRE1) and tumor necrosis factor receptor-associated factor 2 (TRAF2) in CLL cells treated with P1446A, providing insights into upstream regulation of JNK in this setting. Consistent with previous reports on limited functionality of ER stress mechanism in CLL cells, treatment with P1446A failed to induce an extensive unfolded protein response. This study provides rationale for additional investigations of P1446A in CLL.


Protocol for a randomised controlled trial of a web-based healthy relationship tool and safety decision aid for women experiencing domestic violence (I-DECIDE).
Domestic violence is a serious problem affecting the health and wellbeing of women globally. Interventions in health care settings have primarily focused on screening and referral, however, women often may not disclose abuse to health practitioners. The internet offers a confidential space in which women can assess the health of their relationships and make a plan for safety and wellbeing for themselves and their children. This randomised controlled trial is testing the effectiveness of a web-based healthy relationship tool and safety decision aid (I-DECIDE). Based broadly on the IRIS trial in the United States, it has been adapted for the Australian context where it is conducted entirely online and uses the Psychosocial Readiness Model as the basis for the intervention. In this two arm, pragmatic randomised controlled trial, women who have experienced abuse or fear of a partner in the previous 6 months will be computer randomised to receive either the I-DECIDE website or a comparator website (basic relationship and safety advice). The intervention includes self-directed reflection exercises on their relationship, danger level, priority setting, and results in an individualised, tailored action plan. Primary self-reported outcomes are: self-efficacy (General Self-Efficacy Scale) immediately after completion, 6 and 12 months post-baseline; and depressive symptoms (Centre for Epidemiologic Studies Depression Scale, Revised, 6 and 12 months post-baseline). Secondary outcomes include mean number of helpful actions for safety and wellbeing, mean level of fear of partner and cost-effectiveness. This fully-automated trial will evaluate a web-based self-information, self-reflection and self-management tool for domestic violence. We hypothesise that the improvement in self-efficacy and mental health will be mediated by increased perceived support and awareness encouraging positive change. If shown to be effective, I-DECIDE could be easily incorporated into the community sector and health care settings, providing an alternative to formal services for women not ready or able to acknowledge abuse and access specialised services. Trial registered on 15(th) December 2014 with the Australian New Zealand Clinical Trials Registry ACTRN12614001306606.


Body part-centered and full body-centered peripersonal space representations.
Dedicated neural systems represent the space surrounding the body, termed Peripersonal space (PPS), by integrating visual or auditory stimuli occurring near the body with somatosensory information. As a behavioral proxy to PPS, we measured participants' reaction time to tactile stimulation while task-irrelevant auditory or visual stimuli were presented at different distances from their body. In 7 experiments we delineated the critical distance at which auditory or visual stimuli boosted tactile processing on the hand, face, and trunk as a proxy of the PPS extension. Three main findings were obtained. First, the size of PPS varied according to the stimulated body part, being progressively bigger for the hand, then face, and largest for the trunk. Second, while approaching stimuli always modulated tactile processing in a space-dependent manner, receding stimuli did so only for the hand. Finally, the extension of PPS around the hand and the face varied according to their relative positioning and stimuli congruency, whereas the trunk PPS was constant. These results suggest that at least three body-part specific PPS representations exist, differing in extension and directional tuning. These distinct PPS representations, however, are not fully independent from each other, but referenced to the common reference frame of the trunk.


Distribution of Salivary Testosterone in Men and Women in a British General Population-Based Sample: The Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).
Measurement of salivary testosterone (Sal-T) to assess androgen status offers important potential advantages in epidemiological research. The utility of the method depends on the interpretation of the results against robustly determined population distributions, which are currently lacking. To determine age-specific Sal-T population distributions for men and women. Morning saliva samples were obtained from participants in the third National Survey of Sexual Attitudes and Lifestyles, a probability sample survey of the British general population. Sal-T was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear and quantile regression analyses were used to determine the age-specific 2.5th and 97.5th percentiles for the general population (1675 men and 2453 women) and the population with health exclusions (1145 men and 1276 women). In the general population, the mean Sal-T level in men decreased from 322.6 pmol/L at 18 years of age to 153.9 pmol/L at 69 years of age. In women, the decrease in the geometric mean Sal-T level was from 39.8 pmol/L at 18 years of age to 19.5 pmol/L at 74 years of age. The annual decrease varied with age, with an average of 1.0% to 1.4% in men and 1.3% to 1.5% in women. For women, the 2.5th percentile fell below the detection limit (<6.5 pmol/L) from age 52 years onward. The mean Sal-T level was approximately 6 times greater in men than in women, and this remained constant over the age range. The Sal-T level was lowest for men and highest for women in the summer. The results were similar for the general population with exclusions. To our knowledge, this is the first study to describe the sex- and age-specific distributions for Sal-T in a large representative population using a specific and sensitive LC-MS/MS technique. The present data can inform future population research by facilitating the interpretation of Sal-T results as a marker of androgen status.


First Report of Powdery Mildew on Potato Caused by Golovinomyces cichoracearum in California.
In October 2003, potato plants in three fields (cv. Desiree, Satina, Midas, and Mondial) in Lancaster, California exhibited symptoms and signs of powdery mildew. Disease symptoms were most severe on cvs. Desiree and Santina. Disease expression was greater along sprinkler lines and in localized areas from which the disease spread to surrounding plants. Severely affected plants began collapsing just prior to water cutoff. Early symptoms comprise small dark areas on the adaxial surface of leaves, along the veins, and at the petioles. Dark lesions consisting of mycelia and conidiophores were also visible on the main stems of affected plants. As the disease progressed, leaves were covered by a gray powdery fungal mass, and older leaves became necrotic. Conidial chains arising from the hyaline, epiphytic mycelia consisted of two to eight conidia. The cylindric to doliform conidia measured 16.8 to 22.8 μm wide (mean = 19.2, standard error = 0.36, N = 30) × 28.8 to 45.6 μm long (mean = 32.4, standard error = 0.75, N = 30). No cleistothecia were observed. Identification of the causal agent as Golovinomyces cichoracearum (synonyms G. orontii and Erysiphe cichoracearum) based on morphology was confirmed by internal transcribed spacer (ITS)-polymerase chain reaction (PCR). Conidia were washed off the affected leaves, concentrated by filtration and centrifugation, and sonicated to release genomic DNA. PCR was performed on the sonicated conidia with primers ITS4 and ITS5 (2), and the resulting amplicon was purified and sequenced. BLAST analysis of the ITS sequence revealed a 99% homology to E. cichoracearum from an Ambrosia sp. (GenBank Accession No. AF011292). Pathogenicity was confirmed on potato seedlings cv. Red La Soda. Inoculations were performed twice on six plants (three pots) each time. A sterile brush was used to transfer conidia from the affected leaves to seedlings consisting of two to three fully expanded leaves. A plastic bag was placed around each pot containing two seedlings for 1 to 2 days and then removed. Noninoculated controls were stroked with a sterile brush, placed in a plastic bag for 1 to 2 days, and kept in the greenhouse on a separate bench. Two control plants were included for each inoculation. Plants were maintained in a greenhouse at approximately 25 to 28°C and 40 to 60% relative humidity. After 7 days, dark spots were visible on the leaves of all inoculated plants, and conidiophores with conidia identical to those of the isolate used as the inoculum source were apparent after 10 days. The controls showed no disease symptoms or signs. To our knowledge, this is the first report of powdery mildew caused by G. cichoracearum on potato in California. The first field report of the disease was from Washington in 1950 (1), with subsequent reports from Utah and Ohio. References: (1) J. D. Menzies. Plant Dis. Rep. 34:140, 1950. (2) T. J. White et al. PCR Protocols. Academic Press, New York, 1990.


Predictors of throwing velocity in youth and adolescent pitchers.
Shoulder and elbow injuries are a common cause of pain, dysfunction, and inability to play in overhead throwers. Pitch velocity plays an integral part in the etiology of these injuries; however, the demographic and biomechanical correlates with throwing velocity remain poorly understood. We hypothesized that pitchers with higher velocity would have shared demographic and kinematic characteristics. Normal preseason youth and adolescent pitchers underwent dual-orthogonal high-speed video analysis while pitch velocity was collected with a radar gun. Demographic and pitching history data were also collected. Kinematic data and observational mechanics were recorded. Multivariate regression analysis was performed. A total of 420 pitchers were included, with a mean pitching velocity of 64 ± 10 mph. After multivariate logistic regression analysis, the most important correlates with pitch velocity were age (P < .001; R(2) = 0.658), height (P < .001; R(2) = 0.076), separation of the hips and shoulders (P < .001; R(2) = 0.027), and stride length (P < .001; R(2) = 0.016); in combination, these 4 variables explained 78% of the variance in pitch velocity. Each year of age was associated with a mean 1.5 mph increase in velocity; each inch in height, with 1.2 mph; separation of the hips and shoulders, with 2.6 mph; and a 10% increase in stride length, with 1.9 mph. Pitch velocity is most strongly correlated with age, height, separation of the hips and shoulders, and stride length.


Older American Indians' Perspectives on Health, Arthritis, and Physical Activity: Implications for Adapting Evidence-Based Interventions, Oregon, 2013.
Despite the high prevalence of arthritis and physical disability among older American Indians, few evidence-based interventions that improve arthritis self-management via physical activity have been adapted for use in this population. The purpose of this study was to identify beliefs about health, arthritis, and physical activity among older American Indians living in a rural area in Oregon to help select and adapt an arthritis self-management program. In partnership with a tribal health program, we conducted surveys, a focus group, and individual interviews with older American Indians with arthritis. Our sample comprised 6 focus group participants and 18 interviewees. The 24 participants were aged 48 to 82 years, of whom 67% were women. Forms B and C of the Multidimensional Health Locus of Control (MHLC) instrument, modified for arthritis, measured MHLC. The concepts of health, arthritis, and physical activity overlapped in that health was a holistic concept informed by cultural teachings that included living a healthy lifestyle, socializing, and being functionally independent. Arthritis inhibited health and healthy behaviors. Participants identified barriers such as unreliable transportation and recruiting challenges that would make existing interventions challenging to implement in this setting. The Doctor subscale had the highest MHLC (mean = 4.4 [standard deviation (SD), 1.0]), followed by the Internal subscale (3.9 [SD, 1.4]) and the Other People subscale (2.8 [SD, 1.1]). Existing evidence-based programs for arthritis should be adapted to address implementation factors, such as access to transportation, and incorporate cultural values that emphasize holistic wellness and social interconnectedness. Culturally sensitive programs that build on indigenous values and practices to promote active coping strategies for older American Indians with arthritis are needed.


Boarding of Critically Ill Patients in the Emergency Department.
Emergency department boarding is the practice of caring for admitted patients in the emergency department after hospital admission, and boarding has been a growing problem in the United States. Boarding of the critically ill has achieved specific attention because of its association with poor clinical outcomes. Accordingly, the Society of Critical Care Medicine and the American College of Emergency Physicians convened a Task Force to understand the implications of emergency department boarding of the critically ill. The objective of this article is to review the U.S. literature on (1) the frequency of emergency department boarding among the critically ill, (2) the outcomes associated with critical care patient boarding, and (3) local strategies developed to mitigate the impact of emergency department critical care boarding on patient outcomes. Review article. Emergency department-based boarding of the critically ill patient is common, but no nationally representative frequency estimates has been reported. Boarding literature is limited by variation in the definitions used for boarding and variation in the facilities studied (boarding ranges from 2% to 88% of ICU admissions). Prolonged boarding in the emergency department has been associated with longer duration of mechanical ventilation, longer ICU and hospital length of stay, and higher mortality. Health systems have developed multiple mitigation strategies to address emergency department boarding of critically ill patients, including emergency department-based interventions, hospital-based interventions, and emergency department-based resuscitation care units. Emergency department boarding of critically ill patients was common and was associated with worse clinical outcomes. Health systems have generated a number of strategies to mitigate these effects. A definition for emergency department boarding is proposed. Future work should establish formal criteria for analysis and benchmarking of emergency department-based boarding overall, with subsequent efforts focused on developing and reporting innovative strategies that improve clinical outcomes of critically ill patients boarded in the emergency department.


Neighborhood characteristics, adherence to walking, and depressive symptoms in midlife African American women.
African American women have more symptoms of depressed mood than white women. Adverse neighborhood conditions may contribute to these symptoms. Although reductions in depressive symptoms with physical activity have been demonstrated in white adults, little research has examined the mental health benefits of physical activity in African American women. Further, it is unknown whether physical activity can offset the effects of living in disadvantaged neighborhoods on depressive symptoms. The purpose of this study was to examine the relationships among neighborhood characteristics, adherence to a physical activity intervention, and change over time in depressive symptoms in midlife African American women. Two hundred seventy-eight women participated in a home-based, 24-week moderate-intensity walking intervention. Either a minimal treatment (MT) or enhanced treatment (ET) version of the intervention was randomly assigned to one of the two community health centers. Walking adherence was measured as the percentage of prescribed walks completed. Objective and perceived measures of neighborhood deterioration and crime were included. Adjusting for demographics, body mass index (BMI), and depressive symptoms at baseline, walking adherence and objective neighborhood deterioration were associated with significantly lower depressive symptoms, whereas perceived neighborhood deterioration was associated with significantly higher depressive symptoms at 24 weeks. Adherence to walking as well as aspects of the environment may influence depressive symptoms in African American women. In addition to supporting active lifestyles, improving neighborhood conditions may also promote mental health among African American women.


The association between systemic vascular endothelial growth factor and retinopathy of prematurity in premature infants: a systematic review.
Retinopathy of prematurity (ROP), a vasoproliferative disorder exclusive to premature infants is an important cause of childhood blindness. The number of premature infants surviving with this condition is expected to increase globally. Animal models of oxygen-induced retinopathy studies have shown vascular endothelial growth factor (VEGF) to be a key player in the pathogenesis of ROP. This has led to increased use of VEGF antagonist as an alternative treatment for ROP. The purpose of this systematic review is to determine the association between VEGF and ROP in human newborn. The literature review identified 12 studies to date which fulfilled the search criteria. Investigators used cord blood, serum, plasma and tissue samples to investigate the association between ROP and VEGF. Studies that measured VEGF in cord blood found mixed results, with low VEGF (at birth) associated with ROP in one study and no difference noted in two others. Mixed results were also seen in studies determining VEGF in postnatal venous samples. Four studies showed no difference in VEGF level between premature infants with and without ROP, one study showed an increased VEGF level in premature infants with ROP and another study found serum VEGF to be low in premature infants with ROP. The most recent study demonstrated an initial increase in serum VEGF followed by a decline at the time of treatment. These contradictory results indicate that we are yet to fully understand the role of VEGF in human premature infants and question the rationale of treating ROP with anti-VEGF. Anti-VEGF therapy results in systemic effect on serum VEGF levels for up to 2 months and this could have an effect on neurodevelopmental outcome. The effect of this on other developing organs is currently unknown. More studies are required to determine the mechanistic relationships between systemic VEGF and ROP in premature infants.


Unemployment: a social risk factor associated with early ischemic stroke mortality? Results from the Argentinean National Stroke Registry (ReNACer).
Employment is an indicator of socioeconomic status. Unemployment is a worldwide social challenge, especially in emerging countries, accounting for a proportion of the overall higher mortality rates found in these nations. We assessed the relationship between employment status and in-hospital mortality among acute ischemic stroke patients participating in the Argentinean National Stroke Registry (ReNACer), a prospective, country-wide, hospital-based stroke registry aimed at improving quality of stroke care in Argentina. We compared demographic and socioeconomic characteristics, risk factors, acute treatment, and stroke severity between employed and unemployed patients with acute ischemic stroke participating in ReNACer. We developed a multiple logistic regression model to identify predictors of in-hospital mortality. Among the 726 patients with acute ischemic stroke included in the study, 39.5% were unemployed. In-hospital mortality was higher in the patients who were unemployed at the time of the stroke compared with those who were employed (12.0% v 5.0%; P = .003). On multivariate analysis, being unemployed (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.36-7.37; P = .005), stroke severity (OR, 3.54; 95% CI 1.11-10.40; P = .018), and infarct size >15 mm (OR, 2.80; 95% CI, 1.18-6.60; P = .019) were associated with in-hospital mortality after adjusting for relevant covariates. Social factors may influence poor outcomes after stroke. In the present study, unemployment was associated with a higher risk of adjusted in-hospital mortality. Strategies targeting individuals at high risk of cardiovascular diseases and poorer outcomes should be implemented to reduce stroke impact.


Detection of membrane-bound and soluble antigens by magnetic levitation.
Magnetic levitation is a technique for measuring the density and the magnetic properties of objects suspended in a paramagnetic field. We describe a novel magnetic levitation-based method that can specifically detect cell membrane-bound and soluble antigens by measurable changes in levitation height that result from the formation of antibody-coated bead and antigen complex. We demonstrate our method's ability to sensitively detect an array of membrane-bound and soluble antigens found in blood, including T-cell antigen CD3, eosinophil antigen Siglec-8, red blood cell antigens CD35 and RhD, red blood cell-bound Epstein-Barr viral particles, and soluble IL-6, and validate the results by flow cytometry and immunofluorescence microscopy performed in parallel. Additionally, employing an inexpensive, single lens, manual focus, wifi-enabled camera, we extend the portability of our method for its potential use as a point-of-care diagnostic assay.


Reliability of muscle function and sensory perception measurements of the wrist extensors.
This study determined the reliability of muscle function and sensory perception measures of the wrist extensors. The test-retest reliability of the measurements was determined by an intraclass correlation coefficient (ICC), coefficient of variation (CV), standard error of measurements (SEMs), and one-way repeated measures ANOVA using the values collected from 25 young (20.6 +/- 1.3 years) healthy male volunteers on two occasions separated by 1 day. The measures consisted of grip strength, wrist extension strength (WES), range of motion in active and passive wrist flexion and extension, choice reaction time (CRT), vibration sense (VIB), joint position error sense (JPE), cold pain (CP) and heat pain threshold, and pressure pain threshold. An acceptable reliability was determined as the ICC values greater than 0.85, CV less than 15%, and SEMs less than 5%. ICC of all measures except for JPE were greater than 0.85, only CV of JPE, CP, and VIB exceeded 15%, SEMs were higher than 5% only for JPE and CP, and the ANOVA showed a significant time effect for CRT and WES. It is concluded that most of the measurements except JPE are reliable and can be used to investigate effects of a physiotherapy intervention on the wrist extensors.


Metabolic flux analysis using ¹³C peptide label measurements.
¹³C metabolic flux analysis (MFA) has become the experimental method of choice to investigate the cellular metabolism of microbes, cell cultures and plant seeds. Conventional steady-state MFA utilizes isotopic labeling measurements of amino acids obtained from protein hydrolysates. To retain spatial information in conventional steady-state MFA, tissues or subcellular fractions must be dissected or biochemically purified. In contrast, peptides retain their identity in complex protein extracts, and may therefore be associated with a specific time of expression, tissue type and subcellular compartment. To enable 'single-sample' spatially and temporally resolved steady-state flux analysis, we investigated the suitability of peptide mass distributions (PMDs) as an alternative to amino acid label measurements. PMDs are the discrete convolution of the mass distributions of the constituent amino acids of a peptide. We investigated the requirements for the unique deconvolution of PMDs into amino acid mass distributions (AAMDs), the influence of peptide sequence length on parameter sensitivity, and how AAMD and flux estimates that are determined through deconvolution compare to estimates from a conventional GC-MS measurement-based approach. Deconvolution of PMDs of the storage protein β-conglycinin of soybean (Glycine max) resulted in good AAMD and flux estimates if fluxes were directly fitted to PMDs. Unconstrained deconvolution resulted in inferior AAMD and flux estimates. PMD measurements do not include amino acid backbone fragments, which increase the information content in GC-MS-derived analyses. Nonetheless, the resulting flux maps were of comparable quality due to the precision of Orbitrap quantification and the larger number of peptide measurements.


Relationship between psoriasis and non-alcoholic fatty liver disease.
Various components of metabolic syndrome have an important role in the pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and psoriasis, suggesting an association between these diseases. However, at present very few studies have reported on the systematic evaluations of the prevalence of NAFLD in patients with psoriasis disorder. To investigate the prevalence of NAFLD in patients with psoriasis vulgaris. The study also evaluated the parallel relationship between both of the diseases. Patients over18 years old and with a diagnosis of psoriasis vulgaris at the outpatient unit of Department of Dermatology were considered for enrolment and were followed up by the Department of Hepatology, Madras Medical College. Each and every patient completed a questionnaire, underwent a thorough skin evaluation, and had a right upper quadrant ultrasound and fasting blood workup. Two hundred and fifty patients were enrolled in the study. The participants were predominantly middle aged (mean: 44.74 ±11.989 years), overweight (average body mass index (BMI): 24.772 ±3.611 kg/m2), and male (68%, n = 170). The overall prevalence of NAFLD among psoriasis was 45.2%. Non-alcoholic fatty liver disease is highly prevalent among our cohort of patients with psoriasis, occurring in 45.2% of patients. Comorbidity of NAFLD is highly associated with psoriasis, which emphasises that both diseases may develop simultaneously. Health care providers should be mindful of this association since early evaluation and diagnosis of NAFLD in patients with psoriasis may play a vital role in alleviating the progression of liver disease.