Methylation mediated silencing of TMS1/ASC gene in prostate cancer.
Transcriptional silencing associated with aberrant promoter methylation has been established as an alternate pathway for the development of cancer by inactivating tumor suppressor genes. TMS1 (Target of Methylation induced Silencing), also known as ASC (Apoptosis Speck like protein containing a CARD) is a tumor suppressor gene which encodes for a CARD (caspase recruitment domain) containing regulatory protein and has been shown to promote apoptosis directly and by activation of downstream caspases. This study describes the methylation induced silencing of TMS1/ASC gene in prostate cancer cell lines. We also examined the prevalence of TMS1/ASC gene methylation in prostate cancer tissue samples in an effort to correlate race and clinico-pathological features with TMS1/ASC gene methylation. Loss of TMS1/ASC gene expression associated with complete methylation of the promoter region was observed in LNCaP cells. Gene expression was restored by a demethylating agent, 5-aza-2'deoxycytidine, but not by a histone deacetylase inhibitor, Trichostatin A. Chromatin Immunoprecipitation (ChIP) assay showed enrichment of MBD3 (methyl binding domain protein 3) to a higher degree than commonly associated MBDs and MeCP2. We evaluated the methylation pattern in 66 prostate cancer and 34 benign prostatic hyperplasia tissue samples. TMS1/ASC gene methylation was more prevalent in prostate cancer cases than controls in White patients (OR 7.6, p 0.002) while no difference between the cases and controls was seen in Black patients (OR 1.1, p 0.91). Our study demonstrates that methylation-mediated silencing of TMS1/ASC is a frequent event in prostate cancer, thus identifying a new potential diagnostic and prognostic marker for the treatment of the disease. Racial differences in TMS1/ASC methylation patterns implicate the probable role of molecular markers in determining in susceptibility to prostate cancer in different ethnic groups.


Probiotics, infection and immunity.
Taking live bacteria by mouth to improve health (probiotics) is not intuitively rational yet it is a practice with a long history. As interest in the effects on health of the intestinal flora has developed, along with major advances in the technology for studying it, so has come a new interest in establishing the true benefits of probiotic therapy. This review summarizes the most recent contributions to this rapidly developing area. Probiotic bacteria, mainly bifidobacteria and lactobacilli for historical reasons, can prevent or ameliorate some diseases. Many empirical studies have been done, but work to develop the ideal characteristics of probiotics lags behind. Current literature covers survival of probiotics in the gut, mucosal adherence, antibacterial/pathogen mechanisms, effects on immune function and clinical studies. Probiotic bacteria are effective in preventing and reducing the severity of acute diarrhoea in children. They are also useful in antibiotic associated diarrhoea but not for elimination of Helicobacter pylori. In inflammatory bowel disease, especially ulcerative colitis, probiotics offer a safe alternative to current therapy. Probiotics have been used to prevent urogenital tract infection with benefit and, perhaps more intriguingly, to reduce atopy in children. Probiotics do not invariably work and study of mechanisms is urgently needed.


Changes in soil moisture drive soil methane uptake along a fire regeneration chronosequence in a eucalypt forest landscape.
Disturbance associated with severe wildfires (WF) and WF simulating harvest operations can potentially alter soil methane (CH4 ) oxidation in well-aerated forest soils due to the effect on soil properties linked to diffusivity, methanotrophic activity or changes in methanotrophic bacterial community structure. However, changes in soil CH4 flux related to such disturbances are still rarely studied even though WF frequency is predicted to increase as a consequence of global climate change. We measured in-situ soil-atmosphere CH4 exchange along a wet sclerophyll eucalypt forest regeneration chronosequence in Tasmania, Australia, where the time since the last severe fire or harvesting disturbance ranged from 9 to >200 years. On all sampling occasions, mean CH4 uptake increased from most recently disturbed sites (9 year) to sites at stand 'maturity' (44 and 76 years). In stands >76 years since disturbance, we observed a decrease in soil CH4 uptake. A similar age dependency of potential CH4 oxidation for three soil layers (0.0-0.05, 0.05-0.10, 0.10-0.15 m) could be observed on incubated soils under controlled laboratory conditions. The differences in soil CH4 uptake between forest stands of different age were predominantly driven by differences in soil moisture status, which affected the diffusion of atmospheric CH4 into the soil. The observed soil moisture pattern was likely driven by changes in interception or evapotranspiration with forest age, which have been well described for similar eucalypt forest systems in south-eastern Australia. Our results imply that there is a large amount of variability in CH4 uptake at a landscape scale that can be attributed to stand age and soil moisture differences. An increase in severe WF frequency in response to climate change could potentially increase overall forest soil CH4 sinks.


Structure, chromosomal localization, and brain expression of human Cx36 gene.
Rat connexin-36 (Cx36) is the first gap junction protein shown to be expressed predominantly in neuronal cells of the mammalian central nervous system. As a prerequisite for studies devoted to the investigation of the possible role of this connexin in human neurological diseases, we report the cloning and sequencing of the human Cx36 gene, its chromosomal localization, and its pattern of expression in the human brain analyzed by radioactive in situ hybridization. The determination of the human gene sequence revealed that the coding sequence of Cx36 is highly conserved (98% identity at the protein level with the mouse and rat Cx36 and 80% with the ortholog perch and skate Cx35), and that the gene structure is that typical of the Cx35/36 subgroup observed in the other species (presence of a single intron located within the coding region, 71 bp after the translation initiation site). The distribution of Cx36 in several regions of the human central nervous system is similar to that previously observed in rat brain. The most intense signal among the cerebral areas examined by in situ hybridization was observed in the inferior olivary complex, both in principal and accessory nuclei. A moderate labeling was also observed in several myelencephalic nuclei, in specific cells of the the cerebellar cortex, in a relatively large subpopulation of cells in the cerebral cortex, in the hilus of the dentate gyrus, and in the strata radiatum and oriens of hippocampal subfields. Moreover, labeled cells were revealed in all the lamina of the spinal cord gray matter. The chromosomal localization of the human Cx36 gene was determined by fluorescence in situ hybridization. The results allowed assignment of the gene to band 15q14, thus making it a possible candidate gene for a form of familial epilepsy previously linked to the same chromosomal band. The knowledge of the human Cx36 gene sequence, of its chromosomal localization, and of its pattern of expression opens new avenues for the analysis of its possible involvement in human genetic and acquired neuropathology.


Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats.
To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. These alterations may reflect the obesity-related insulin resistance commonly observed in human NIDDM.


Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials.
Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. We identified 8 randomized controlled trials (n = 462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55-39.18; P < .00001), total cholesterol by 24.18% (18.54-29.83; P < .00001), very low-density lipoprotein cholesterol by 21.59% (9.16-34.02; P = .0007), non-high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92-37.74; P < .00001), and triglycerides by 36.26% (22-50.54; P < .00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39-3.04; P = .0003), flu-like symptoms (1.63; 1.22-2.17; P = .0008), alanine aminotransferase ≥3X upper limit of normal (4.44; 1.67-11.86; P = .003), and hepatic steatosis (3.85, 1.39-10.67; P = .01). The risks of alanine aminotransferase ≥10X upper limit of normal did not reach statistical significance (1.57; 0.32-7.6, P = .58). Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo.


Inhibitors of tyrosine phosphorylation induce apoptosis in human leukemic cell lines.
Experimental evidence suggests that hematopoietic growth factors promote cell survival by suppressing apoptosis or programmed cell death. Since interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) induce tyrosine phosphorylation of a common set of proteins in the factor-dependent cell line M07e, we have investigated whether growth-factor-induced tyrosine phosphorylation is involved in the promotion of cell survival and suppression of apoptosis. Experiments were carried out with the leukemic cell lines HL-60 and M07e and the tyrosine kinase inhibitors genistein and tyrphostin AG82. Both the tyrosine kinase inhibitors induced apoptosis of HL-60 and M07e cells. This was indicated by the appearance of DNA degradation and morphologic evidence of nuclear condensation and fragmentation. It was also confirmed by flow cytometry of DNA, which showed apoptotic cells as a fraction of cells characterized by a diminished DNA stainability, represented on the DNA frequency histograms as a distinct peak below the G0/G1 population. Kinase inhibitors also reduced the fraction of cells in the S phase of the cell cycle. That tyrphostin specifically inhibited tyrosine kinases was further suggested by the prevention of its effects by the tyrosine phosphatase inhibitor sodium orthovanadate (vanadate), at least during the first 18-24 h of treatment. The incomplete prevention of genistein effects by vanadate suggests that genistein is a less specific inhibitor of tyrosine kinases than tyrphostin, and may also act as an inhibitor of topoisomerase II. Vanadate also prevented apoptosis and reduction of the S phase in M07e cells cultured for 24 h in the absence of growth factors. These results suggest that tyrosine phosphorylation is an essential step in IL-3 and GM-CSF signal transduction. Since in our experimental model the effects of tyrosine kinase inhibition and growth factor deprivation could be reversed by concomitant inhibition of tyrosine phosphatases, it is suggested that a balance between tyrosine kinases and tyrosine phosphatases establishes whether a cell will survive or undergo apoptosis.


Occupational physical activity in relation with prostate cancer and benign prostatic hyperplasia.
Using data from two case-control studies undertaken in Athens, Greece from 1994 to 1997, we have examined the association of occupational physical activity with the risk of prostate cancer and benign prostatic hyperplasia (BPH). Cases consisted of 320 patients with histologically confirmed incident prostate cancer and 184 patients with surgically treated BPH. Controls were 246 patients hospitalized for minor conditions. Occupations before retirement were classified, independently and blindly as to case-control status, into high, medium, and low physical activity levels. After fine controlling for years of schooling, there was a suggestive inverse association of physical activity with prostate cancer (P for trend 0.12) and a significant one with BPH (P for trend 0.04). The odds ratio (95% confidence interval) for high versus low activity was 0.69 (0.40-1.22) for prostate cancer and 0.59 (0.31-1.11) for BPH. The association of physical activity with both conditions tended to be more pronounced among men 65 years old or younger. Given the high frequency of occurrence of the examined conditions in the male population and our limited knowledge about other modifiable risk factors, preventive measures may have to focus on increasing physical activity.


[Neurologic syndromes in children with phakomatosis].
The author studied 189 patients with the main forms of phakomatosis (Louis-Barre syndrome, Sturge-Weber, Hippel-Lindau disease and Recklinghausens neurofibromatosis.) The use of pathogenetical treatment in the Louis-Barre syndrome (a transplantation of a neonatal thymus with the bone marrow) promoted an improvement in the clinico-immunological indices. A study of familial forms of the Louis-Barre syndrome and the Sturge-Weber disease demonstrated a similarity according to the main clinical indices among the sibs in 80% which may speak of the role of the genetical factors in the formation of the disease.


A myocardin-related transcription factor regulates activity of serum response factor in Drosophila.
Serum response factor (SRF) regulates genes involved in cell proliferation, migration, cytoskeletal organization, and myogenesis. Myocardin and myocardin-related transcription factors (MRTFs) act as powerful transcriptional coactivators of SRF in mammalian cells. We describe an MRTF from Drosophila, called DMRTF, which shares high homology with the functional domains of mammalian myocardin and MRTFs. DMRTF forms a ternary complex with and stimulates the activity of Drosophila SRF, which has been implicated in branching of the tracheal (respiratory) system and formation of wing interveins. A loss-of-function mutation introduced into the DMRTF locus by homologous recombination results in abnormalities in tracheal branching similar to those in embryos lacking SRF. Misexpression in wing imaginal discs of a dominant negative DMRTF mutant also causes a diminution of wing interveins, whereas overexpression of DMRTF results in excess intervein tissue, abnormalities reminiscent of SRF loss- and gain-of-function phenotypes, respectively. Overexpression of these DMRTF mutants in mesoderm and in the tracheal system also perturbs mesoderm cell migration and tracheal branching, respectively. We conclude that the interaction of MRTFs with SRF represents an ancient protein partnership involved in cytoplasmic outgrowth and cell migration during development.


Efficacy of treatment of equine anhidrosis with acupuncture and Chinese herbs is low but higher in treated horses compared with placebo.
To assess the therapeutic efficacy of acupuncture in combination with Chinese herbs for treatment of horses affected with anhidrosis. 44 horses affected with anhidrosis for up to 3 years' duration were enrolled. Inclusion required both compatible clinical signs and results of a quantitative intradermal terbutaline sweat test. Study horses were randomly allocated into 2 groups. Group 1 (n = 19) was treated with daily Chinese herbs and 4 weekly acupuncture sessions. Group 2 (n = 25) was given daily hay powder as a placebo and 4 weekly sham acupuncture sessions. Horses were tested by quantitative intradermal terbutaline sweat test within 2 days after treatment completion and again 4 weeks following treatment. Terbutaline-induced sweat responses (mg) were not different between groups within 2 days and 4 weeks after treatment. Two days after treatment, ratios of sweat responses (compared to baseline) were higher (P < .05) in the treatment group compared to the placebo group at terbutaline concentrations of 1.0, 100, and 1,000 µg/mL. The number of horses responding to treatment was higher in the treatment group (5/19 [26%]), compared to horses in the placebo group (1/25 [4%]) for 1 of 5 terbutaline concentrations 2 days (10 µg/mL) or 4 weeks (0.1 µg/mL) after treatment. Ratios of sweat responses were higher in treatment horses 2 days after treatment, compared to baseline, but not 4 weeks later. The efficacy of a traditional Chinese veterinary medicine protocol for anhidrosis treatment with acupuncture and Chinese herbs was low but higher in treated horses compared with placebo.


Collagen synthesis in connective tissue of wounded rat mesentery: effect of dietary zinc deficiency.
The effect of dietary zinc deficiency of two weeks duration on the synthesis of collagen and of other proteins in wounded rat mesentery was investigated 1, 3, 5, 7, and 10 days after operation. Collagen synthesis was maximal on postoperative day 5. There were no significant differences between zinc-deficient and pair-fed control rats at any time in either collagen synthesis or that of other protein. On the contrary, zinc-deficient rats tended to synthesise more protein than control rats. Collagen concentration (measured as hydroxyproline) in scar tissue on day 10 did not differ between zinc-deficient and control rats. In summary, the earlier reported decreased collagen/protein synthesis associated with zinc deficiency seems to be region dependent.


[Acquired bullous epidermolysis and multiple myeloma].
A case of epidermolysis bullosa acquisita (EBA) with negative direct immunofluorescence and multiple myeloma is reported. Epidermolysis bullosa acquisita has been associated with several systemic diseases, but only three cases diagnosed of EBA have been associated with multiple myeloma in the literature.


Effects of inter-character spacing on saccade programming in beginning readers and dyslexics.
The present study investigated the impact of inter-character spacing on saccade programming in beginning readers and dyslexic children. In two experiments, eye movements were recorded while dyslexic children, reading-age, and chronological-age controls, performed an oculomotor lateralized bisection task on words and strings of hashes presented either with default inter-character spacing or with extra spacing between the characters. The results of Experiment 1 showed that (1) only proficient readers had already developed highly automatized procedures for programming both left- and rightward saccades, depending on the discreteness of the stimuli and (2) children of all groups were disrupted (i.e., had trouble to land close to the beginning of the stimuli) by extra spacing between the characters of the stimuli, and particularly for stimuli presented in the left visual field. Experiment 2 was designed to disentangle the role of inter-character spacing and spatial width. Stimuli were made the same physical length in the default and extra-spacing conditions by having more characters in the default spacing condition. Our results showed that inter-letter spacing still influenced saccade programming when controlling for spatial width, thus confirming the detrimental effect of extra spacing for saccade programming. We conclude that the beneficial effect of increased inter-letter spacing on reading can be better explained in terms of decreased visual crowding than improved saccade targeting.


Chemical energetics of force development, force maintenance, and relaxation in mammalian smooth muscle.
High-energy phosphate utilization (delta approximately P) associated with force development, force maintenance, and relaxation has been determined during single isometric tetani in the rabbit taenia coli. ATP resynthesis from glycolysis and respiration was stopped without deleterious effects on the muscle. At 18 degrees C and a muscle length of 95% l0, the resting rate of energy utilization is 1.8 +/- 0.2 nmol/g . s-1, or 0.85 +/- 0.2 mmol approximately P/mol of total creatine (Ct) . s-1, where Ct = 2.7 mumol/g wet wt. During the initial 25 s of stimulation when force is developed, the average rate of delta approximately P was -8.2 +/- 0.8 mmol/mol Ct . s-1, some four times greater than during the subsequent 35 s of force maintenance, when the rate was -2.0 +/- 0.6 mmol approximately P/mol Ct . s-1. The energy cost of force redevelopment (0 to 95% P0) after a quick release from the peak of a tetanus is very low compared with the initial force development. Therefore, the high rate of energy utilization during force development is not due only to internal work done against the series elasticity nor to any high rate of cross-bridge cycling inherently associated with force development. The high economy of force maintenance compared with other muscle types is undoubtedly due to a slower cross-bridge cycle time. The energy utilization during 45 s of relaxation was not statistically significant, and integral of Pdt/delta approximately P was higher during relaxation than during force maintenance in the stimulated muscle.


Phosphorylating DNA with DNA.
Nearly 50 individual DNAs with polynucleotide kinase-like activity were isolated from a random-sequence pool by using in vitro selection. Each self-phosphorylating deoxyribozyme makes use of one or more of the eight standard NTPs or dNTPs as a source of activated phosphate. Although most prototypic deoxyribozymes poorly differentiate between the ribose and deoxyribose moieties, further optimization by in vitro selection produced variants that display up to 100-fold discrimination between related NTP and dNTP substrates. An optimized ATP-dependent deoxyribozyme uses ATP >40,000-fold more efficiently than CTP, GTP, or UTP. This enzyme operates with a rate enhancement of nearly one billion-fold over the uncatalyzed rate of ATP hydrolysis. A bimolecular version of the ATP-dependent deoxyribozyme was further engineered to phosphorylate specific target DNAs with multiple turnover. The substrate-recognition patterns and rate enhancements intrinsic to these DNAs are characteristic of naturally occurring RNA and protein enzymes, supporting the hypothesis that DNA has sufficient catalytic potential to function as an enzyme in biological systems.


The role of the immune system in lung transplantation: towards improved long-term results.
Over the past 35 years, lung transplantation has evolved from an experimental treatment to the treatment of choice for patients with end-stage lung disease. Beyond the immediate period after lung transplantation, rejection and infection are the leading causes of death. The risk of rejection after lung transplantation is generally higher than after other solid organ transplants, and this necessitates more intensive immunosuppression. However, this more intensive treatment does not reduce the risk of rejection sufficiently, and rejection is one of the most common complications after transplantation. There are multiple forms of rejection including acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. These have posed a vexing problem for clinicians, patients, and the field of lung transplantation. Confounding matters is the inherent effect of more intensive immunosuppression on the risk of infections. Indeed, infections pose a direct problem resulting in morbidity and mortality and increase the risk of chronic lung allograft dysfunction in the ensuing weeks and months. There are complex interactions between microbes and the immune response that are the subject of ongoing studies. This review focuses on the role of the immune system in lung transplantation and highlights different forms of rejection and the impact of infections on outcomes.


Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse.
Advanced glycation end products (AGEs), known promoters of diabetic complications, form abundantly in heated foods and are ingested in bioreactive forms. To test whether dietary AGEs play a role in the progression of insulin resistance, C57/BL/KsJ db/db mice were randomly placed for 20 weeks on a diet with either a low AGE content (LAD) or a 3.4-fold higher content of AGE (high AGE diet [HAD]), including (epsilon)N-carboxymethyllysine (CML) and methylglyoxal (MG). LAD-fed mice showed lower fasting plasma insulin levels throughout the study (P = 0.01). Body weight was reduced by approximately 13% compared with HAD-fed mice (P = 0.04) despite equal food intake. LAD-fed mice exhibited significantly improved responses to both glucose (at 40 min, P = 0.003) and insulin (at 60 min, P = 0.007) tolerance tests, which correlated with a twofold higher glucose uptake by adipose tissue (P = 0.02). Compared with the severe hypertrophy and morphological disorganization of islets from HAD-fed mice, LAD-fed mice presented a better-preserved structure of the islets. LAD-fed mice demonstrated significantly increased plasma HDL concentrations (P < 0.0001). Consistent with these observations, LAD-fed mice exhibited twofold lower serum CML and MG concentrations compared with HAD-fed mice (P = 0.02). These results demonstrate that reduced AGE intake leads to lower levels of circulating AGE and to improved insulin sensitivity in db/db mice.


Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers.
HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63-1.50 hours and slowly eliminated with a terminal half-life of 21.12-40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing.


Antigenic differences among Campylobacter fetus S-layer proteins.
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of S-layer proteins extracted from Campylobacter fetus strains by using acid glycine buffer showed that the predominant S-layer proteins of different strains had subunit molecular weights in the range of 90,000 to 140,000. Electron microscopy revealed oblique S-layer lattices with a spacing of approximately 5.6 nm (gamma = 75 degrees) on wild-type strains VC1, VC119, VC202, and VC203. Three variants of C. fetus VC119 producing a predominant S-layer subunit protein of different molecular weight (Mr) from that of the parent were also examined. Each variant produced an oblique lattice morphologically indistinguishable from that of the parent. Amino-terminal sequence analysis showed that the S-layer proteins of the VC119 parent and variants were identical up to residue 18 and that this sequence differed from but was related to the first 16 N-terminal residues shared by the S-layer proteins of the three other wild-type C. fetus isolates. Western immunoblot analysis with an antiserum prepared to the VC119 protein and an antiserum prepared to C. fetus 84-40 LP (Z. Pei, R. T. Ellison, R. V. Lewis, and M. J. Blaser, J. Biol. Chem. 263:6416-6420, 1988) showed that strains of C. fetus were capable of producing S-layer proteins with at least four different antigenic specificities. Immunoelectron microscopy with antiserum to the VC119 S-layer protein showed that C. fetus cultures contained cells with immunoreactive oblique S-layer lattices as well as cells with oblique S-layer lattices which did not bind antibody. This suggests that C. fetus S-layer proteins undergo antigenic variation. Thermal denaturation experiments indicated that the antigenicity conferred by the surface-exposed C. fetus S-layer epitopes was unusually resistant to heat, and the thermal stability appeared to be due to the highly organized lattice structure of the S. layer. Protease digestion of purified VC119 S-layer protein revealed a trypsin-, chymotrypsin-, and endoproteinase Glu-C-resistant domain with an apparent Mr of 110,000, which carried the majority of the epitopes of the S-layer protein, and a small enzyme-sensitive domain. The trypsin- and chymotrypsin-resistant polypeptides shared an overlapping sequence which differed from the N-terminal sequence of the intact S-layer protein.


Hospital ethical climate and teamwork in acute care: the moderating role of leaders.
Health care delivery teams have received much attention in recent years from researchers and practitioners. Recent empirical research has demonstrated that objective and subjective outcomes tend to be improved when care teams function smoothly and efficiently. However, little is known about how the work environment, or care context, influences team processes that lead to better outcomes. The purposes of this study were to explore acute care staff's perceptions of how two components of the work environment, the ethical climate and continuous quality improvement leadership, influence teamwork and to begin to identify actionable approaches for improving teamwork. Although ethical climate influences have been studied in several sectors, research is lacking in health care. A cross-sectional field study explored how the ethical climate impacted teamwork in an acute care setting and how continuous quality improvement leadership behaviors moderated the relationship between the ethical climate and teamwork. Results indicated that clinicians who perceived the ethical climate to be benevolent were significantly more likely to say that teamwork was better. Furthermore, we found that continuous quality improvement leadership styles moderated the relationship between the ethical climate and teamwork. Although a benevolent ethical climate appears to be associated with effective teamwork, it appears that the proximate continuous quality improvement behaviors exhibited by leaders have a significant impact as well, above and beyond the climate. Implications for research and practice are discussed.


pH affects fruiting and slug orientation in Dictyostelium discoideum.
We have demonstrated two interesting facts about the transition from the migration stage to the final fruiting stage of Dictyostelium discoideum. One is that fruiting is favoured on acid substrata, and secondly, migrating slugs tend to migrate towards the acid side of a pH gradient. The suggestion is offered that these results can be interpreted in terms of the effects of NH3. It appears to be an additional mechanism (besides phototaxis and thermotaxis) to assure that the final fruiting takes place in a favourable environment.


Classical and membrane-initiated estrogen signaling in an in vitro model of anterior hypothalamic kisspeptin neurons.
The neuropeptide kisspeptin is essential for sexual maturation and reproductive function. In particular, kisspeptin-expressing neurons in the anterior rostral periventricular area of the third ventricle are generally recognized as mediators of estrogen positive feedback for the surge release of LH, which stimulates ovulation. Estradiol induces kisspeptin expression in the neurons of the rostral periventricular area of the third ventricle but suppresses kisspeptin expression in neurons of the arcuate nucleus that regulate estrogen-negative feedback. To focus on the intracellular signaling and response to estradiol underlying positive feedback, we used mHypoA51 cells, an immortalized line of kisspeptin neurons derived from adult female mouse hypothalamus. mHypoA51 neurons express estrogen receptor (ER)-α, classical progesterone receptor (PR), and kisspeptin, all key elements of estrogen-positive feedback. As with kisspeptin neurons in vivo, 17β-estradiol (E2) induced kisspeptin and PR in mHypoA51s. The ERα agonist, 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, produced similar increases in expression, indicating that these events were mediated by ERα. However, E2-induced PR up-regulation required an intracellular ER, whereas kisspeptin expression was stimulated through a membrane ER activated by E2 coupled to BSA. These data suggest that anterior hypothalamic kisspeptin neurons integrate both membrane-initiated and classical nuclear estrogen signaling to up-regulate kisspeptin and PR, which are essential for the LH surge.


The design plan of kinesin motors.
The kinesin superfamily comprises a large and structurally diverse group of microtubule-based motor proteins that produce a variety of force-generating activities within cells. This review addresses how the structures of kinesin proteins provide clues as to their biological functions and motile properties. We discuss structural features common to all kinesin motors, as well as specialized features that enable subfamilies of related motors to carry out specialized activities. We also discuss how the kinesin motor domain uses chemical energy from ATP hydrolysis to move along microtubules.


Non-fungible tokens in healthcare: a scoping review.
Non-Fungible Tokens (NFTs) are digital assets that are verified using blockchain technology to ensure authenticity and ownership. NFTs have the potential to revolutionize healthcare by addressing various issues in the industry. The goal of this study was to identify the applications of NFTs in healthcare. Our scoping review was conducted in 2023. We searched the Scopus, IEEE, PubMed, Web of Science, Science Direct, and Cochrane scientific databases using related keywords. The article selection process was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). After applying inclusion and exclusion criteria, a total of 13 articles were chosen. Then extracted data was summarized and reported. The most common application of NFTs in healthcare was found to be in health data management with 46% frequency, followed by supply chain management with 31% frequency. Furthermore, Ethereum is the main blockchain platform that is applied in NFTs in healthcare with 70%. The findings from this review indicate that the NFTs that are currently used in healthcare could transform it. Also, it appears that researchers have not yet investigated the numerous potentials uses of NFTs in the healthcare field, which could be utilized in the future.


A pivotal role for heat shock protein 90 in Ewing sarcoma resistance to anti-insulin-like growth factor 1 receptor treatment: in vitro and in vivo study.
Ewing Sarcoma (ES) shows several deregulated autocrine loops mediating cell survival and proliferation. Therefore, their blockade is a promising therapeutic approach. We previously reported the in vitro effect of insulin-like growth factor 1 receptor (IGF1R)/KIT pathway blockade on ES cell lines, and we now extend our observations to changes induced by this treatment in interacting proteins/networks. A proteomic analysis revealed that Heat Shock Protein (HSP)90 was differentially expressed between ES cell lines sensitive and resistant to specific IGF1R/KIT inhibitors. We therefore inhibited HSP90 with 17-allylamino-17-demethoxygeldanamycin (17-AAG) and siRNA, and observed that ES cell line growth and survival were reduced, especially in the resistant cell lines. Conversely, HSP90 induced-expression conferred resistance to anti-IGF1R/KIT treatment in the sensitive cell lines. 17-AAG treatment induced HSP90 client protein degradation, including AKT, KIT, or IGF1R, by inhibiting their physical interaction with HSP90. Xenograft models developed with A673 ES cell line confirmed that HSP90 inhibition, alone or combined with IGF1R inhibition, significantly reduced tumor growth and expression of client proteins. Remarkably, using two independent clinical sample sets, we have found that nearly half of IGF1R-positive tumors also show HSP90 overexpression. This delineates a subset of patients that could benefit from combination of anti-HSP90 agents when considering IGF1R-targeting therapies. Importantly, sensitivity to drugs such as ADW/IMA depends not only on the levels of expression and basal activation of IGF1R/KIT, but also, and for the first time reported in ES, on the development of the stress response mechanism. Accordingly, HSP90 expression could be a predictive factor of response to IGF1R-targeting therapies.


Bloodstream Infections Caused by Magnusiomyces capitatus and Magnusiomyces clavatus: Epidemiological, Clinical, and Microbiological Features of Two Emerging Yeast Species.
Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. Our objectives were to determine the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. In seven institutions, a total of 34 Magnusiomyces BSI were identified. Identification was done by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/L), followed by posaconazole (MIC50, 0.125/0.25 mg/L). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, low essential agreement between gradient test and microdilution was recorded for all antifungals (0 to 70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.


P2Y12 inhibitor monotherapy in complex percutaneous coronary intervention: A post-hoc analysis of SMART-CHOICE randomized clinical trial.
It remains unclear whether P2Y12 monotherapy, especially clopidogrel, following short-duration dual antiplatelet therapy (DAPT) is associated with favorable outcomes in patients undergoing complex percutaneous coronary intervention (PCI). Therefore, this study analyzed the efficacy and safety of P2Y12 inhibitor monotherapy, mostly clopidogrel (78%), in complex PCI following short-term DAPT. The post-hoc analysis of the SMART-CHOICE trial involving 2,993 patients included 498 cases of complex PCIs, defined by at least one of the following features: 3 vessels treated, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation with ≥ 2 stents implanted, and a total stent length of ≥ 60 mm. The primary endpoint was major adverse cardiac and cerebrovascular event (MACCE), defined as the composite of all-cause death, myocardial infarction, and stroke. The primary safety endpoint included bleeding, defined as Bleeding Academic Research Consortium (BARC) types 2 to 5. Complex PCI group had a higher risk of MACCE (4.0% vs. 2.3%, hazard ratio [HR] = 1.74, 95% confidence interval [CI]: 1.05-2.89, p = 0.033) and a similar risk of BARC types 2-5 bleeding (2.6% vs. 2.6%, HR = 1.02, 95% CI: 0.56-1.86, p = 0.939) compared with those without complex PCIs. Patients undergoing complex PCIs, followed by P2Y12 inhibitor monotherapy and 12 months of DAPT exhibited similar rates of MACCE (3.8% vs. 4.2%, HR = 0.92, 95% CI: 0.38-2.21, p = 0.853). P2Y12 inhibitor monotherapy, mostly clopidogrel, following 3 months of DAPT did not increase ischemic events in patients with complex PCIs.


Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil.
The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor.


Plate tectonics influence on geogenic arsenic cycling: From primary sources to global groundwater enrichment.
More than 100 million people around the world are endangered by geogenic arsenic (As) in groundwater, residing in sedimentary aquifers. However, not all sedimentary aquifers are groundwater As enriched, and the ultimate source of As in enriched aquifer sediments is yet-unknown, globally. A reconnaissance of the major aquifers suggests that major As enriched aquifers are predictably systematic on a global scale, existing in sedimentary foreland basins in the vicinity of modern or ancient orogenic systems. In conformity with the Principle of Uniformitarianism, we demonstrate that the groundwater As comes from magmatic arcs (primary source) in present (e.g. Andes) or ancient (e.g. Himalaya) continental convergent margins of some of the most prominent orogenic systems across the globe, and ends up in sediments (secondary source) in adjoining foreland or related basins that eventually act as aquifers. These arc magmas scavenge As while rising through the deep continental crust. Erosion of such orogens ultimately increases the bulk As content in sediments of adjoining basins, leading to groundwater As enrichment in downstream aquifers. Such As-polluted aquifers are eventually extensively used for groundwater exploitation, for drinking and other human purposes. Surface geological and biogeochemical processes, like redox reactions, are conducive to such groundwater As enrichment. We suggest this model by integrating our study of long-time observations in Himalayan and Andean basin aquifers, and generalizing 63 major aquifers across the globe, to demonstrate the source-to-sink transport of As, thereby delineating it's geogenic cycling in the subsurface. This work outlines the specifics of the mechanisms that would drive the processes of groundwater As enrichment across spatio-temporal scales, i.e. tectonic-scale taking place over millions of years on continental-scale and groundwater pollution taking place at human time-scales on village to household scale. Thus, in this work, we demonstrate a direct evidence of connectivity between global geological processes and individual human health.


Comparison of R-wave detection errors of four wireless heart rate belts in the presence of noise.
Four commercial wireless chest belts (Vetta, Nashbar, Polar and new Polar) were assessed for their susceptibility to noises in R-wave detection. A normal ECG signal was generated using a LionHeart simulator (Bio-tek Instruments, Inc.) with a fixed RR interval (750 ms) and R-wave amplitude (1 mV). Different levels of EMG and baseline wanderings (sinusoidal waves) were recorded from a healthy subject and a Quartec Model MFG-1 generator, respectively. They were added to the ECG signal in a BioPac system (BioPac systems Inc., Santa Barbara, CA) to simulate an ECG in physiological noise. The BioPac system applied the 'contaminated' ECG to the belts via a voltage divider. A PC-based Polar Precision Performance system was used to receive the detected R-wave pulses transmitted from the wireless belts and to calculate the RR intervals. Two types of detection errors were observed in the RR intervals: small time shifts, the potentially non-fixable small variance, and missed/false beats, the abnormally large and potentially fixable intervals. Results showed that small time shifts exist in all tests ranging from -10 ms to 10 ms and increase with the level of EMG before missed/false beats occur. Missed/false beats occur only when EMG level is beyond the threshold of 0.4 mV, 1.6 mV, 1.2 mV and 1.2 mV for Vetta, Nashbar, Polar and new Polar, respectively. The potential to detect and fix EMG introduced missed/false beats showed that this type of error could only be improved when the added EMG was below a certain value. Results also showed that no missed/false beats occur when the frequency and amplitude of sinusoidal waves were below 1 Hz and 5 mV.


Fungi isolated from flue-cured tobacco sold in Southeast United States, 1968-1970.
Flue-cured tobacco leaves, from low- and middle-stalk positions, offered for sale in each of two markets, within each of five tobacco types, were evaluated for moisture content (MC) and filamentous fungi during August through October in 1968, 1969, and 1970. Alternaria alternata, Penicillium cyclopium, Aspergillus niger, Aspergillus repens, and Aspergillus flavus were most frequently isolated from cultured tissue. Other filamentous fungi that grew from the tissue included species from four genera of field fungi and seven species of storage fungi. Although the MC ranged from 11.0 to 22.5%, it averaged 16.4, 16.8, and 15.9% for samples taken in 1968, 1969, and 1970, respectively. Average populations of fungi per sample over the three years ranged from 0 to 1,528,500 colonies/g of tobacco.


Comparison of 30 microgram and 120 microgram gentamicin disks for the prediction of gentamicin resistance in Enterococcus faecalis.
Single strain regression analysis was performed on PDM II medium for E. faecalis with 10, 30 and 120 micrograms gentamicin disks using E. faecalis, strain ATCC 29212 as the reference. This method permits the calculation of zone diameters corresponding to different MIC values for different disk contents. The lack of discrimination between normal low-level resistant strains and high-level resistance using the 10 micrograms disk was confirmed. However, both the 30 micrograms and 120 micrograms disks seemed to provide a separation of the normal low-level gentamicin-resistant population from strains with increased resistance. Since the 30 micrograms disk is used routinely in some countries, there should be no need for an extra high content disk in these laboratories. This was confirmed when 96 clinical isolates of E. faecalis were analysed and the results of routine disk diffusion tests were compared with the MIC values. Two of the strains showed high-level gentamicin resistance (greater than 2000 mg/l) and produced no zone of inhibition. The other 94 isolates showed gentamicin MIC values between 4-16 mg/l, and 72 of the MIC results were 8 mg/l. The zone diameters for these strains ranged between 15 and 25 mm with a mean of 18.2 and a median value of 18 mm. In order to include statistical considerations of the zone size populations for setting of breakpoints, a study of gentamicin zone size distributions was performed for several bacterial species. Inhibition zone diameter values around the 30 micrograms gentamicin disk for 2079 clinical isolates of E. faecalis, 2268 S. aureus, 3201 E. coli and 547 strains of P. mirabilis from different years were plotted as histograms. Tests for agreement with a Gaussian distribution showed that the histograms were slightly peaked and skewed towards higher zone values. Parametric and non-parametric statistical tests were compared and the results showed that means and medians were very similar and that parametric fractile estimations at the lower end of the histogram populations were conservative and could be used in view of a slightly lower rate of false resistance. The 1% parametric fractile of 12 mm was selected as a suitable breakpoint for the identification of normal, low-level resistant isolates of E. faecalis using the standardized disk test of the Swedish Reference Group for Antibiotics.


Low doses of aprotinin in aortocoronary bypass surgery--advantages and disadvantages.
Excessive blood loss, as a result of augmented postoperative drainage, is considered one of the most serious cardiosurgical complications. The compounding constitutive anemia seems particularly harmful for patients with coronary artery disease. Aprotinin (Trasylol), a non-specific serine protease inhibitor, is successfully used to reduce excessive postoperative bleeding in such patients. The aim of our study was to verify the hypothesis whether aprotinin used during cardiopulmonary bypass procedure affects hemostatic parameters, which might be crucial for the elevated risk of thromboembolic complications. The group of 54 patients subjected to coronary artery surgical treatment included 30 patients, who were given intraoperatively 3 million KIU aprotinin each, and 24 subjects non-treated with aprotinin. Aliquots of blood were withdrawn at several time intervals, until the 5th day after the operation. Whole blood platelet activation and reactivity (the expressions of P-selectin and glycoprotein Ib) were monitored by means of flow cytometry. In addition, several plasma parameters, like PAI-1, t-PA, D-dimers, prothrombin fragment F1 + 2, fibrinogen, ATIII activity, troponin I and CK-MB, as well as platelet count were determined at each time point. In this study we confirmed the essential advantage of the use of aprotinin: both the postoperative blood drainage and the blood units to be transfused postoperatively to cardiosurgical patients were vastly reduced in the aprotinin-treated subjects. The enhanced overall frequency of perioperative myocardial infarction events was not attributed to this group of patients, nor the non Q-wave infarctions were observed more often in patients treated with aprotinin. In these patients, fibrinolysis parameters tended to be depressed (with increased PAI-1 dominating over elevated t-PA) on the first day after the operation, and no significant differences with regard to fibrinogen, prothrombin fragment F1 + 2, troponin I and platelet count. There was a continuous rise in D-dimers in all the postoperative patients, which lasted until the third day and tended to reach plateau at the 5th day after the operation. We failed to reveal the preventive effects of aprotinin on platelet function: both platelet activation and reactivity remained apparently unchanged. Overall, our results rather support the reasoning on the advantageous effects of low doses of aprotinin. The use of this inhibitor reduces the risk of postoperative undesirable bleeding and results in a decreased postoperative drainage and reduced transfused blood units. On the other hand, however, a higher incidence of perioperative Q-wave infarction in the aprotinin-treated patients, although purely apparent and not statistically significant, might question the unlimited safety of the use of aprotinin in cardiovascular operations.


A comprehensive scientific overview of Garcinia cambogia.
The fruit rind of Garcinia gummi-gutta, commonly known as Garcinia cambogia (syn.), is extensively used traditionally as a flavourant in fish curries due to its sharp sour taste. Additional ethnobotanical uses include its use as a digestive and a traditional remedy to treat bowel complaints, intestinal parasites and rheumatism. This small fruit, reminiscent of a pumpkin in appearance, is currently most popularly used and widely advertised as a weight-loss supplement. Studies have shown that the extracts as well as (-)-hydroxycitric acid (HCA), a main organic acid component of the fruit rind, exhibited anti-obesity activity including reduced food intake and body fat gain by regulating the serotonin levels related to satiety, increased fat oxidation and decreased de novo lipogenesis. HCA is a potent inhibitor of adenosine triphosphate-citrate lyase, a catalyst for the conversion process of citrate to acetyl-coenzyme A, which plays a key role in fatty acid, cholesterol and triglycerides syntheses. The crude extract or constituents from the plant also exerted hypolipidaemic, antidiabetic, anti-inflammatory, anticancer, anthelmintic, anticholinesterase and hepatoprotective activities in in vitro and in vivo models. Phytochemical studies of various plant parts revealed the presence of mainly xanthones (e.g. carbogiol) and benzophenones (e.g. garcinol) together with organic acids (e.g. HCA) and amino acids (e.g. gamma aminobutyric acid). Currently, a large number of G. cambogia/HCA dietary supplements for weight management are being sold although the possible toxicity associated with the regular use of these supplements has raised concerns. In most cases, complaints have been related to multicomponent formulations and at this stage G. cambogia has not been confirmed as the potentially toxic culprit. This review presents a scientific overview of G. cambogia with reference to relevant botanical aspects, ethnobotanical uses, phytochemistry and biological activity as well as toxicity.


Mortality and survival of COVID-19.
This study aims to identify the risk factors associated with mortality and survival of COVID-19 cases in a state of the Brazilian Northeast. It is a historical cohort with a secondary database of 2070 people that presented flu-like symptoms, sought health assistance in the state and tested positive to COVID-19 until 14 April 2020, only moderate and severe cases were hospitalised. The main outcome was death as a binary variable (yes/no). It also investigated the main factors related to mortality and survival of the disease. Time since the beginning of symptoms until death/end of the survey (14 April 2020) was the time variable of this study. Mortality was analysed by robust Poisson regression, and survival by Kaplan-Meier and Cox regression. From the 2070 people that tested positive to COVID-19, 131 (6.3%) died and 1939 (93.7%) survived, the overall survival probability was 87.7% from the 24th day of infection. Mortality was enhanced by the variables: elderly (HR 3.6; 95% CI 2.3-5.8; P < 0.001), neurological diseases (HR 3.9; 95% CI 1.9-7.8; P < 0.001), pneumopathies (HR 2.6; 95% CI 1.4-4.7; P < 0.001) and cardiovascular diseases (HR 8.9; 95% CI 5.4-14.5; P < 0.001). In conclusion, mortality by COVID-19 in Ceará is similar to countries with a large number of cases of the disease, although deaths occur later. Elderly people and comorbidities presented a greater risk of death.


Angiomatous lymphoid hamartoma: inhibitory effects on erythropoiesis, growth, and primary hemostasis.
An 11-year-old boy was noted to have microcytic anemia, growth retardation, polyclonal hypergammaglobulinemia, and abnormal platelet function. An angiomatous lymphoid hamartoma was removed from the retroperitoneal space. Postoperatively the child exhibited a dramatic growth spurt and complete resolution of the abnormal laboratory measurements. Studies were performed before and after tumor removal to investigate the nature of the associated anemia, growth retardation, and altered hemostasis. There was no evidence of iron deficiency, thalassemia, or an antierythropoietin factor. Prolonged bleeding time and impaired ristocetin-induced platelet aggregation normalized following tumor resection. Serum obtained before surgery inhibited lymphocyte proliferation in mixed lymphocyte culture as well as fibroblast growth in vitro. Detailed study of growth regulatory hormones failed to reveal significant alterations except for significantly reduced somatomedin which normalized after surgery. The factor(s) which inhibit in vitro cellular growth and lower in vivo plasma somatomedin concentration remain unknown.


Population genetic structure of Aedes aegypti, the principal vector of dengue viruses.
Knowledge of vector population genetic structure is critical for vector-borne disease control and prevention strategies. Advances in both molecular genotyping technology and theoretical developments have contributed to the growing impact of such approaches on medical entomology. The pattern of genetic structure may affect the design of control strategies in determining appropriate control limits necessary to disrupt pathogen transmission. In this review, we focus on the mosquito Aedes aegypti, the primary vector of dengue viruses. We describe and discuss numerous population genetic studies illustrating the local genetic variation and gene flow of Ae. aegypti populations.


Perioperative management of a patient with left ventricular dysfunction and anomalous coronary arteries.
Anesthetic management of patients with coronary artery disease undergoing noncardiac surgery is quite challenging. Such patients are at increased risk of perioperative cardiac complications and death. We report an illustrative case of a 62-year-old male with ischemic heart disease and anomalous coronary arteries for obstructed paraumbilical hernia repair.


Medical education in the Caribbean: variability in medical school programs and performance of students.
The purpose of this study was to examine the structure of medical training programs in the Caribbean and the performance of the students. There are 56 medical schools in 16 countries currently recognized and open in the Caribbean. Almost 30,000 students from this region applied for exams leading to Educational Commission for Foreign Medical Graduates (ECFMG) certification between 1993 and 2007. The authors summarized school characteristics and pass rates on United States Medical Licensing Examinations, by country. The structure of medical education varies across the region, including existence of accrediting bodies and review processes. First-attempt pass rates by country ranged from 19.4% to 84.4% for Step 1, from 26.3% to 79.7% for the Step 2 Clinical Knowledge Examination, and from 60.6% to 97.2% for the Step 2 Clinical Skills Examination. There is significant variability in undergraduate medical education and the performance of students of medical schools in Caribbean nations.


Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia.
Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/-), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling.


Effects of initial abstinence and programmed lapses on the relative reinforcing effects of cigarette smoking.
Fifty-eight smokers received abstinence-contingent monetary payments for 1 (n=15) or 14 (n=3) days. Those who received contingent payments for 14 days also received 0, 1, or 8 experimenter-delivered cigarette puffs on 5 evenings. The relative reinforcing effects of smoking were assessed in a 3-hr session on the final study day, when participants made 20 choices between smoking or money. The reinforcement contingencies exerted robust control over smoking, and programmed smoking lapses produced few discernible effects. These results further illustrate the robust control that reinforcement contingencies can exert over cigarette smoking and suggest that any effects of lapses on the relative reinforcing effects of smoking are modest under conditions involving abstinence-contingent reinforcement contingencies.


Tobacco-related instruction in undergraduate nursing education in Illinois.
Tobacco use is responsible for more deaths in the United States than any other factor. Nurses are in a unique position to convey life-saving messages to clients regarding tobacco use. To gauge the type and extent of tobacco-related background knowledge acquired by nurses in the course of their education, the Nurses' Committee of the Illinois Division of the American Cancer Society (ACS) surveyed 70 nursing programs in the state of Illinois. The number of lecture hours spent on tobacco-related issues was greater in LPN programs than in either associate or baccalaureate degree programs, and instruction was scattered throughout the curriculum of each program. Most schools reported heavy reliance on adult medical-surgical textbooks to convey tobacco-related content. The most recent editions of the textbooks used by the schools were reviewed, and they also were found to adopt a scattered approach, with a disappointing lack of depth regarding the hazards of tobacco. It is recommended a single course be identified as responsible for relaying tobacco-related content and information supplied by general medical-surgical textbooks be supplemented by materials drawn from other sources.


Randomized, double-blind, placebo-controlled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese encephalitis vaccine.
Japanese encephalitis (JE) is the most important mosquito-borne viral encephalitis and has a high case fatality rate. It is caused by Japanese encephalitis virus. Improved vaccines are urgently needed for residents in countries of endemicity, travelers, and the military. The aim of the present trial was to evaluate the safety and tolerability of IC51, Intercell's Vero cell-derived, purified, inactivated JE vaccine. This was a randomized (3:1), double-blind, placebo-controlled, multicenter phase 3 trial. Healthy subjects were randomized to receive 2 doses of IC51 (n=2012) or placebo (n=663) at a 4-week interval. Adverse events following immunization (AEFI) were documented over a period of 2 months. The rate of severe AEFI was similar in the IC51 group (0.5%) and the placebo group (0.9%). The rate of medically attended AEFI and all AEFI was also similar in the IC51 group and the placebo group. The same applied for all adverse events, including local and systemic tolerability. Importantly, there were no signs of acute allergic reactions. The Intercell JE vaccine IC51 had a safety profile similar to that of placebo. These data, together with the immunogenicity data from a recent phase 3 trial, form the basis of application for licensure of this vaccine. ClinicalTrials.gov identifier: NCT00605058.


Quality of Life of Food-Allergic Patients Before, During, and After Oral Immunotherapy.
Oral immunotherapy (OIT) for food allergy is demanding but data on patients' quality of life (QOL) throughout the process are limited. To characterize changes in QOL of food-allergic patients during and after OIT. In a prospective cohort study, the Food Allergy Quality of Life Questionnaire-Parental Form (FAQLQ-PF) was administered to parents of 191 consecutive children aged 4 to 12 years undergoing OIT for food allergy. Questionnaires were administered at OIT initiation, mid up-dosing, upon reaching maintenance, and after 6 months of follow-up. Age- and sex-matched food-allergic children (n = 48) not undergoing OIT served as controls. FAQLQ-PF scores had significantly improved (decreased) from OIT initiation to reaching full maintenance (emotional impact [EI], 3.66-3.32, P = .001; food anxiety [FA], 3.90-3.32, P < .001; social and dietary limitation [SDL], 3.50-2.94, P < .001; and total score, 3.69-3.19, P < .001) and partial maintenance, whereas no change was noted in control patients. Worse baseline QOL, single food allergy, and a younger age predicted greater QOL improvement. Of the 85 (88.5%) patients who completed the FAQLQ-PF at mid up-dosing and for whom QOL deteriorated, a significant improvement was noted upon reaching maintenance. Additional significant improvement in QOL was observed in the 95 (88.8%) patients who completed the FAQLQ-PF 6 months after reaching maintenance (EI, 3.414-2.993, P = 0.049; FA, 3.37-2.593, P = .001; SDL, 2.989-2.264, P = .001; and total score, 3.266-2.614, P = .001). The QOL of food-allergic children improves significantly upon reaching OIT maintenance, with additional improvement 6 months later. The detrimental effect of OIT on some patients' QOL during up-dosing is reversed upon reaching maintenance.


Structural and Crystallographic Information from 61Ni Solid-State NMR Spectroscopy: Diamagnetic Nickel Compounds.
Despite the significance of nickel compounds, NMR spectroscopy of the active nickel isotope 61Ni remains a largely unexplored field. While nickel(0) compounds have been studied by 61Ni NMR in solution, solid-state experiments have been limited to Knight shift studies of nickel metal and nickel intermetallics. In conjunction with an NMR study of their ligands and 61Ni relativistic computations, the first 61Ni solid-state NMR (SSNMR) spectra of diamagnetic compounds are reported here. Specifically, bis(1,5-cyclooctadiene)nickel(0) [Ni(cod)2], tetrakis(triphenylphosphite)nickel(0) [Ni[P(OPh)3]4], and tetrakis(triphenylphosphine)nickel(0) [Ni(PPh3)4] were studied. 61Ni SSNMR spectra of Ni(cod)2 were used to determine its isotropic chemical shift (δiso = 965 ± 10 ppm), span (Ω = 1700 ± 50 ppm), skew (κ = -0.15 ± 0.05), quadrupolar coupling constant (CQ = 2.0 ± 0.3 MHz), quadrupolar asymmetry parameter (η = 0.5 ± 0.2), and the relative orientation of the chemical shift and electric field gradient tensors. A solution study of Ni(cod)2 in C6D6 yielded a narrow 61Ni signal, and the temperature dependence of δiso(61Ni) was assessed (δiso being 936.5 ppm at 295 K). The solution is proposed as a secondary chemical shift reference for 61Ni NMR in lieu of the extremely toxic Ni(CO)4 primary reference. For Ni[P(OPh)3]4, 61Ni SSNMR was used to infer the presence of two distinct crystallographic sites and establish ranges for δiso in the solid state, as well as an upper bound for CQ (3.5 MHz for both sites). For Ni(PPh3)4, line shape fitting provided a δiso value of 515 ± 10 ppm, Ω of 50 ± 50 ppm, κ of 0.5 ± 0.5, CQ of 0.05 ± 0.01 MHz, and η of 0.0 ± 0.2. The study of Ni(PPh3)4, in particular, demonstrates the utility of 61Ni SSNMR given the lack of a previously reported crystal structure and transient nature of Ni(PPh3)4 in solution.


Differences of prefrontal cortex activity between picture-based personality tests: a near-infrared spectroscopy study.
This study reports on brain activity induced by picture-based personality tests. Near-infrared spectroscopy is a newly developed, noninvasive technology in neuroimaging that can measure brain activity through blood volume changes. We measure the prefrontal cortex (Brodmann Area 10 [BA10]) activities of adolescents during the Rorschach (1921), the Rosenzweig Picture-Frustration Study (PFS; Hayashi, 1964), and Thematic Apperception Test (TAT; Murray, 1943). BA10 showed that the PFS was left-hemisphere dominant and significantly different from the Rorschach and TAT, which showed a tendency to be right-hemisphere dominant. We believe that this tendency reflects emotion and sociality.


G-quadruplex DNA-based asymmetric catalysis of michael addition: Effects of sonication, ligands, and co-solvents.
There is an escalating interest of using double stranded DNA molecules as a chiral scaffold to construct metal-biomacromolecule hybrid catalysts for asymmetric synthesis. Several recent studies also evaluated the use of G-quadruplex DNA-based catalysts for asymmetric Diels-Alder and Friedel-Crafts reactions. However, there is still a lack of understanding of how different oligonucleotides, salts (such as NaCl and KCl), metal ligands and co-solvents affect the catalytic performance of quadruplex DNA-based hybrid catalysts. In this study, we aim to systematically evaluate these key factors in asymmetric Michael addition reactions, and to examine the conformational and molecular changes of DNA by circular dichroism (CD) spectroscopy and gel electrophoresis. We achieved up to 95% yield and 50% enantiomeric excess (ee) when the reaction of 2-acylimidazole 1a and dimethylmalonate was catalyzed by 5'-G3 (TTAG3 )3 -3' (G4DNA1) in 20 mM MOPS (pH 6.5) containing 50 mM KCl and 40 µM [Cu(dmbipy)(NO3 )2 ], and G4DNA1 was pre-sonicated in ice bath for 10 min prior to the reaction. G-quadruplex-based hybrid catalysts provide a new tool for asymmetric catalysis, but future mechanistic studies should be sought to further improve the catalytic efficiency. The current work presents a systematic study of asymmetric Michael addition catalyzed by G-quadruplex catalysts constructed via non-covalent complexing, and an intriguing finding of the effect of pre-sonication on catalytic efficiency. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:891-898, 2016.


Air pollution exposure--a trigger for myocardial infarction?
The association between ambient air pollution exposure and hospitalization for cardiovascular events has been reported in several studies with conflicting results. A case-crossover design was used to investigate the effects of air pollution in 660 first-time myocardial infarction cases in Stockholm in 1993-1994, interviewed shortly after diagnosis using a standard protocol. Air pollution data came from central urban background monitors. No associations were observed between the risk for onset of myocardial infarction and two-hour or 24-hour air pollution exposure. No evidence of susceptible subgroups was found. This study provides no support that moderately elevated air pollution levels trigger first-time myocardial infarction.


Ultrasonographic and Myotonometric Evaluation of the Shoulder Girdle After an Isokinetic Muscle Fatigue Protocol.
The aim of the study was to investigate supraspinatus tendon thickness, acromiohumeral distance (AHD), and stiffness/creep measures of the shoulder girdle in overhead asymptomatic athletes in muscle fatigue conditions. Observational, case series study. Biomechanics and motion analysis lab. Twenty-four male overhead volleyball (n = 8), handball (n = 8), and tennis (n = 8) athletes. All subjects were without shoulder injury history. The subjects were tested for supraspinatus tendon thickness (in short and long axis), AHD using ultrasound scans and stiffness/creep of upper trapezius, infraspinatus, anterior and posterior deltoid, and pectoralis major using the myotonometer device before and immediately after a fatigue protocol. The fatigue protocol consisted of 3 sets of 32 maximum isokinetic concentric contractions performing shoulder internal and external rotation at isokinetic speed of 120°/s. A significant increase in supraspinatus tendon thickness (both in short and long axis) (P = .045 and P = .01, respectively) and a reduction in AHD (P = .01) were found after an isokinetic protocol. The stiffness increased significantly in upper trapezius (P ≤ .01), infraspinatus (P = .003), posterior deltoid (P = .047), and pectoralis major (P = .01), whereas the creep showed a significant decrement for upper trapezius (P = .001) and infraspinatus (P = .003). The present study has demonstrated the postexercise fatigue in overhead athletes. The increase of stiffness (reduction of muscle creep) and tendon thickness (simultaneous to the reduction of AHD) may indicate rotator cuff overloading as a primary intrinsic tendon pathology process.


weHelp: A Reference Architecture for Social Recommender Systems.
Recommender systems have become increasingly popular. Most of the research on recommender systems has focused on recommendation algorithms. There has been relatively little research, however, in the area of generalized system architectures for recommendation systems. In this paper, we introduce weHelp: a reference architecture for social recommender systems - systems where recommendations are derived automatically from the aggregate of logged activities conducted by the system's users. Our architecture is designed to be application and domain agnostic. We feel that a good reference architecture will make designing a recommendation system easier; in particular, weHelp aims to provide a practical design template to help developers design their own well-modularized systems.


Metal binding properties of Escherichia coli YjiA, a member of the metal homeostasis-associated COG0523 family of GTPases.
GTPases are critical molecular switches involved in a wide range of biological functions. Recent phylogenetic and genomic analyses of the large, mostly uncharacterized COG0523 subfamily of GTPases revealed a link between some COG0523 proteins and metal homeostasis pathways. In this report, we detail the bioinorganic characterization of YjiA, a representative member of COG0523 subgroup 9 and the only COG0523 protein to date with high-resolution structural information. We find that YjiA is capable of binding several types of transition metals with dissociation constants in the low micromolar range and that metal binding affects both the oligomeric structure and GTPase activity of the enzyme. Using a combination of X-ray crystallography and site-directed mutagenesis, we identify, among others, a metal-binding site adjacent to the nucleotide-binding site in the GTPase domain that involves a conserved cysteine and several glutamate residues. Mutations of the coordinating residues decrease the impact of metal, suggesting that metal binding to this site is responsible for modulating the GTPase activity of the protein. These findings point toward a regulatory function for these COG0523 GTPases that is responsive to their metal-bound state.


Fast-SL: an efficient algorithm to identify synthetic lethal sets in metabolic networks.
Synthetic lethal sets are sets of reactions/genes where only the simultaneous removal of all reactions/genes in the set abolishes growth of an organism. Previous approaches to identify synthetic lethal genes in genome-scale metabolic networks have built on the framework of flux balance analysis (FBA), extending it either to exhaustively analyze all possible combinations of genes or formulate the problem as a bi-level mixed integer linear programming (MILP) problem. We here propose an algorithm, Fast-SL, which surmounts the computational complexity of previous approaches by iteratively reducing the search space for synthetic lethals, resulting in a substantial reduction in running time, even for higher order synthetic lethals. We performed synthetic reaction and gene lethality analysis, using Fast-SL, for genome-scale metabolic networks of Escherichia coli, Salmonella enterica Typhimurium and Mycobacterium tuberculosis. Fast-SL also rigorously identifies synthetic lethal gene deletions, uncovering synthetic lethal triplets that were not reported previously. We confirm that the triple lethal gene sets obtained for the three organisms have a precise match with the results obtained through exhaustive enumeration of lethals performed on a computer cluster. We also parallelized our algorithm, enabling the identification of synthetic lethal gene quadruplets for all three organisms in under 6 h. Overall, Fast-SL enables an efficient enumeration of higher order synthetic lethals in metabolic networks, which may help uncover previously unknown genetic interactions and combinatorial drug targets. The MATLAB implementation of the algorithm, compatible with COBRA toolbox v2.0, is available at https://github.com/RamanLab/FastSL CONTACT: firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Development of the immunofluorescent antibody test for detection of feline leukemia virus infection in cats.
Studies of the immunodetection of various microorganisms by various assay systems indicated that the most specific and sensitive assays are immunofluorescence, radioimmunoassay, and immunoblot analysis (western blot), followed by sensitive but less specific ELISA and agglutination assays and, finally, by even less sensitive but very specific virus isolation and double immunodiffusion techniques. The first test for the clinical detection of FeLV infection in pet cats was the immunofluorescent antibody (IFA) test, which was introduced in 1972. The FeLV test is used for detection for FeLV infection and not as a test for leukemia or any other feline disease. The IFA test was compared with an immunodiffusion (ID) test and with tissue culture isolation (TCI) of the virus in 26 cats to establish a standard for FeLV tests. Excellent correlation was observed between the IFA and the ID tests (100%).


Virulence and citrulline ureidase activity of Pasteurella tularensis.
Marchette, Nyven J. (University of Utah, Salt Lake City), and Paul S. Nicholes. Virulence and citrulline ureidase activity of Pasteurella tularensis. J. Bacteriol. 82:26-32. 1961.-The presence of a citrulline ureidase system in Pasteurella tularensis strains of high virulence, and its absence in avirulent strains and strains of low virulence was confirmed. The presence of this system, however, was shown to be not directly related to virulence. The only wild strain of P. tularensis tested that lacked a citrulline ureidase system was isolated from a rodent. All the strains, isolated from rabbits, rabbit ticks, a human being, and a horse, that were tested possessed this system. The existence of two North American varieties of P. tularensis was postulated on the basis of virulence and citrulline ureidase activity.


A cascade signal-amplified fluorescent biosensor combining APE1 enzyme cleavage-assisted target cycling with rolling circle amplification.
A cascade signal-amplified fluorescent biosensor was developed for miRNA-21 detection by combining APE1 enzyme-assisted target recycling and rolling circle amplification strategy. A key feature of this biosensor is its dual-trigger mechanism, utilizing both tumor-endogenous miRNA-21 and the APE1 enzyme in the initial amplification step, followed by a second rolling circle amplification reaction. This dual signal amplification cascade significantly enhanced sensitivity, achieving a detection limit of 3.33 pM. Furthermore, this biosensor exhibited excellent specificity and resistance to interference, allowing it to effectively distinguish and detect the target miRNA-21 in the presence of multiple interfering miRNAs. Moreover, the biosensor maintained its robust detection capabilities in a 10% serum environment, demonstrating its potential for clinical disease diagnosis applications.


Impact of soaking and cooking treatments on the physicochemical and antioxidant properties of parboiled and non-parboiled rice (Oryza sativa L.).
The effects of soaking and cooking on the physicochemical properties and bioactive compounds of two parboiled and non-parboiled rice cultivars (BRRI-28 and Katari bhog) were investigated in this study. Total phenolic content (TPC) increased significantly (p ≤ 0.5) after soaking, while total flavonoid content (TFC) and proanthocyanidin content (PC) decreased significantly (p ≤ 0.5) compared to untreated rice samples. TPC increased by around 23% and 20% in parboiled BRRI 28 and Katari bhog rice extracts, respectively, due to the cooking process, while TFC and PC decreased significantly. DPPH radical scavenging increased whereas reducing power activity decreased after soaking and cooking in parboiled BRRI 28. After processing, the protein, starch, and amylose content of all samples decreased in the majority of cases. After being soaked, all samples L * and b * values increased as compared to raw rice samples. As a result, it can be concluded that the treatment of soaking and cooking of parboiled rice (BRRI-28) was suitable to improve the antioxidant properties as compared to non-parboiled rice.


Molecular anatomy of an onychophoran: compartmentalized sperm storage and heterogeneous paternity
Onychophorans (peripatus or velvet worms) show extraordinarily high local endemism, and cryptic species are common. As part of a programme addressing issues of endemicity at hierarchical spatial scales, we investigated reproduction in Euperipatoides rowelli (Onychophora: Peripatopsidae) using microsatellite analysis. This species is ovoviviparous, and females have up to 70 embryos in their uteri simultaneously. Batches of undeveloped and well-developed embryos may be present in the uteri of a female. Paired ovaries lead via a common oviduct into paired uteri, each of which has a spermatheca (sperm storage organ). Insemination in E. rowelli is dermal-haemocoelic: spermatophores are placed on the skin of the female, the body wall is breeched, and sperm are released into the haemocoel through which they migrate to the spermathecae. There is no obvious mechanism to prevent sperm mixing, yet microsatellite analysis indicated that offspring in a female's paired reproductive tracts can be sired by different males, and that the paired spermathecae can contain sperm from different males. More than 70% of females had broods with multiple paternity. The data are consistent with the potential for female postcopulatory influence over fertilizations: in particular, compartmentalization of sperm from different males into different spermathecae. Female control of fertilizations could lead to benefits including increased diversity of offspring, minimization of maternal-paternal genetic incompatibility, and influence on offspring genotypes. Multiple mating alone may increase the genetic diversity of offspring: this could be of importance in E. rowelli, which has very small genetic neighbourhoods and low genetic marker diversity.


Bio-jETI: a service integration, design, and provisioning platform for orchestrated bioinformatics processes.
With Bio-jETI, we introduce a service platform for interdisciplinary work on biological application domains and illustrate its use in a concrete application concerning statistical data processing in R and xcms for an LC/MS analysis of FAAH gene knockout. Bio-jETI uses the jABC environment for service-oriented modeling and design as a graphical process modeling tool and the jETI service integration technology for remote tool execution. As a service definition and provisioning platform, Bio-jETI has the potential to become a core technology in interdisciplinary service orchestration and technology transfer. Domain experts, like biologists not trained in computer science, directly define complex service orchestrations as process models and use efficient and complex bioinformatics tools in a simple and intuitive way.


Lipopolysaccharide-induced interleukin 8 production by human whole blood is enhanced by epinephrine and inhibited by hydrocortisone.
To determine the effect of epinephrine and hydrocortisone on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production, human whole blood was stimulated with LPS in the presence or absence of these stress hormones. Epinephrine caused a dose-dependent increase in LPS-induced IL-8 production, which was mediated exclusively via beta-adrenergic receptors, as reflected by the facts that beta (but not alpha) receptor blockade reversed the epinephrine effect and beta (but not alpha) receptor stimulation reproduced the epinephrine effect. Further, elevating cellular cyclic AMP (cAMP) concentrations, a known effect of beta-adrenergic stimulation, by addition of dibutyryl cAMP also enhanced LPS-induced IL-8 production. Epinephrine-induced upregulation of IL-10 production masked an even more pronounced stimulating effect of this hormone on IL-8 synthesis, as indicated by the finding that the extent of IL-8 upregulation was greater in the presence of anti-IL-10 than in the absence of anti-IL-10. Hydrocortisone dose-dependently inhibited LPS-induced IL-8 production and reversed epinephrine-induced enhancement of IL-8 production. Epinephrine and hydrocortisone have opposite effects on IL-8 production, which may be relevant for the understanding of endogenous and therapeutic stress hormone influences on IL-8 mediated inflammation.


Effect of Heat Stress on Concentrations of Faecal Cortisol Metabolites in Dairy Cows.
The negative impact of heat stress on health and productivity of dairy cows is well known. Heat stress can be quantified with the temperature-humidity index (THI) and is defined as a THI ≥ 72. Additionally, animal welfare is affected in cows living under heat stress conditions. Finding a way to quantify heat stress in dairy cows has been of increasing interest over the past decades. Therefore, the objective of this study was to evaluate concentrations of faecal glucocorticoid metabolites [i.e. 11,17-dioxoandrostanes (11,17-DOA)] as an indirect stress parameter in dairy cows without heat stress (DOA 0), with heat stress on a single day (acute heat stress, DOA 1) or with more than a single day of heat stress (chronic heat stress, DOA 2). Cows were housed in five farms under moderate European climates. Two statistical approaches (approach 1 and approach 2) were assessed. Using approach 1, concentrations of faecal 11,17-DOA were compared among DOA 0, DOA 1 and DOA 2 samples regardless of their origin (i.e. cow, unpaired comparison with a one-way anova). Using approach 2, a cow was considered as its own control; that is 11,17-DOA was treated as a cow-specific factor and only paired samples were included in the analysis for this approach (paired comparison with t-tests). In approach 1 (p = 0.006) and approach 2 (p = 0.038), 11,17-DOA values of cows under acute heat stress were higher compared to those of cows without heat stress. Our results also indicate that acute heat stress has to be considered as a confounder in studies measuring faecal glucocorticoid metabolites in cows to evaluate other stressful situations.


Tuberculous cerebellar abscess.
Tuberculosis is an important illness with an increasing occurrence. Although considered primarily a pulmonary disease, tuberculosis can affect any organ system. Central nervous system involvement is potentially devastating and occurs with escalating frequency in both immunocompetent and immunologically incompetent populations. This case report involved a patient admitted to the authors' inpatient service. Data were obtained from the patient's medical record. MEDLINE and Index Medicus literature searches were conducted for the years 1977 to the present, with cross-references for earlier articles. A 36-year-old previously healthy, immunocompetent woman with a diagnosis of extrapulmonary tuberculosis and no determined primary focus was found to have a cerebellar abscess. Treatment included surgical excision of the abscess combined with 6 months of antituberculosis therapy. Diagnostic tools included the tuberculosis skin test, smears and culture of specimens, computed tomographic scans, and rapid assays based on nucleic acid amplification, ie, polymerase chain reaction. The polymerase chain reaction has great potential for rapid diagnosis of Mycobacterium tuberculosis, particularly when there might be few bacilli, as in pleural, peritoneal, or cerebrospinal fluid. Appropriate therapy for tuberculous cerebellar abscess includes standard antituberculosis medications for 6 to 9 months and surgical excision of the abscess.


Qualitative study exploring healthy eating practices and physical activity among adolescent girls in rural South Africa.
Dietary behaviours and physical activity are modifiable risk factors to address increasing levels of obesity among children and adolescents, and consequently to reduce later cardiovascular and metabolic disease. This paper explores perceptions, attitudes, barriers, and facilitators related to healthy eating and physical activity among adolescent girls in rural South Africa. A qualitative study was conducted in the rural Agincourt subdistrict, covered by a health and sociodemographic surveillance system, in Mpumalanga province, South Africa. Semistructured "duo-interviews" were carried out with 11 pairs of adolescent female friends aged 16 to 19 years. Thematic content analysis was used. The majority of participants considered locally grown and traditional foods, especially fruits and vegetables, to be healthy. Their consumption was limited by availability, and these foods were often sourced from family or neighbourhood gardens. Female caregivers and school meal programmes facilitated healthy eating practices. Most participants believed in the importance of breakfast, even though for the majority, limited food within the household was a barrier to eating breakfast before going to school. The majority cited limited accessibility as a major barrier to healthy eating, and noted the increasing intake of "convenient and less healthy foods". Girls were aware of the benefits of physical activity and engaged in various physical activities within the home, community, and schools, including household chores, walking long distances to school, traditional dancing, and extramural activities such as netball and soccer. The findings show widespread knowledge about healthy eating and the benefits of consuming locally grown and traditional food items in a population that is undergoing nutrition transition. Limited access and food availability are strong barriers to healthy eating practices. School meal programmes are an important facilitator of healthy eating, and breakfast provision should be considered as an extension of the meal programme. Walking to school, cultural dance, and extramural activities can be encouraged and thus are useful facilitators for increasing physical activity among rural adolescent girls, where the prevalence of overweight and obesity is increasing.


Noteworthy Neurological Manifestations Associated With COVID-19 Infection.
March 11, 2020 marked the start of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19, caused by severe acute respiratory syndrome coronavirus 2, was being reported as a severe respiratory illness. However, since the recognition of this novel virus, there has been a constant realization that it may present or manifest in a multitude of ways. At first, the typical signs and symptoms were what one would expect from a respiratory virus: cough, shortness of breath, and fever. However, as the disease became more prevalent, neurologic symptoms were reported such as headaches, hypogeusia, and hyposmia. This case report aims to add to the growing body of neurologic manifestations by presenting two cases, Bell's palsy and Guillain-Barre syndrome. Each case involves flaccid paralysis as the primary presentation.


Perioperative considerations for patient safety during cosmetic surgery - preventing complications.
Maintaining patient safety in the operating room is a major concern of surgeons, hospitals and surgical facilities. Circumventing preventable complications is essential, and pressure to avoid these complications in cosmetic surgery is increasing. Traditionally, nursing and anesthesia staff have managed patient positioning and safety issues in the operating room. As the number of office-based procedures in the plastic surgeon's practice increases, understanding and implementing patient safety guidelines by the plastic surgeon is of increasing importance.A review of the Joint Commission's Universal Protocol highlights requirements set forth to prevent perioperative complications. In the present paper, the importance of implementing these guidelines into the cosmetic surgery practice is reviewed. Key aspects of patient safety in the operating room are outlined, including patient positioning, ocular protection and other issues essential for minimization of postoperative morbidity. Additionally, as the demand for body contouring surgery in the cosmetic practice continues to increase, special attention to safety considerations specific to the obese and massive weight loss patients is mandatory.After review of the present paper, the reader should be able to introduce the Joint Commission's Universal Protocol into their daily practice. The reader will understand key aspects of patient positioning, airway management and ocular protection in cosmetic surgery. Finally, the reader will have a better understanding of the perioperative care of unique populations including the morbidly obese, massive weight loss patients and the elderly. Attention to detail in these aspects of patient safety can help avoid unnecessary complication and significantly improve the patient's experience and surgical outcome.


Heroin and the illegal drug overdose death epidemic: A history of missed opportunities and resistance.
Due to prohibitionist policies and practices, a poisoned illegal drug supply, and inadequate access to flexible substitution programs, Canada is currently experiencing the worst illegal drug overdose death epidemic in its history. In examining past policies, practices, and discourse that support heroin regulation and drug prohibition, the drivers of the current illegal drug overdose death epidemic in Canada are brought more clearly into focus. This article provides a critical socio-historical analysis of heroin (opioid) regulation with a focus on Canadian federal and provincial policies in the province of B.C., especially the city of Vancouver. Drawing from primary and secondary sources, this article provides a critical socio-historical analysis of heroin (opioid) regulation in Canada. Examining Canada's history of heroin criminalization provides a window to understand the systemic discrimination against people who use illegal heroin and other opioids. From its inception, heroin prohibition has worked to brutally punish a small segment of the population, especially those who are poor, racialized, and gendered. Negative heroin discourse and stereotyping about people who use heroin had an effect, shaping drug law, policing, prisons, and policy and treatment options. Little attention has been given to the increase in heroin possession offences across Canada over nine consecutive years and the lack of heroin substitution programs. Resistance to drug prohibition and criminal approaches to drug use emerged in the 1950s and continue today. Those most affected by drug policies demand inclusion and representation, access to a legal heroin supply, and the establishment and maintenance of heroin buyer clubs, contesting the very foundations of drug control in the twenty-first century.