Inflammatory bowel disease: Efficient remission maintenance is crucial for cost containment.
The inflammatory bowel diseases (IBD) are chronic incurable inflammatory disorders of the gut. Some 10% run a downhill course, requiring emergency medical support and often surgery; another small subset are monogenic, and, threatening pediatric patients, are the challenge of these days. The majority of the IBDs, however, are polygenic low-penetrance diseases, running a lifetime waxing-and-waning course. The prevalent trend is towards a slow worsening and steady cost increase. Each and all drugs of the available arsenal exhibit strengths and weaknesses: Mesalamines are chiefly effectively for mild-moderate colitis, and do not work in Crohn's; steroids do not control some 40% of the ulcerative colitis cases, and are not indicated for Crohn's; thiopurines are effective in the maintenance of the IBDs but do not prevent relapses on withdrawal; biologics are still being used empirically (not monitored) causing further increase of their cost over that of hospitalization. Against all these caveats, two simple rules still hold true: Strict adherence maintenance and avoidance of colitogenic drugs. This matter is expanded in this minireview.


Burkitt'S lymphoma mimicking a primary gynecologic tumor.
Burkitt's lymphoma (BL) occurs mostly in children; bilateral ovarian involvement mimicking a gynecologic malignancy in adults is extremely rare. Here, we report a patient with BL mimicking a gynecologic tumor. A 50-year-old Taiwanese woman presented with the complaint of persistent lower abdominal distension with dull pain, easy satiety, and progressively increasing abdominal girth for 2 weeks. Amenorrhea was also noted for about 2 months, and her review of systems was negative for the common "B" symptoms associated with lymphoma. At our hospital, imaging studies revealed a huge pelvic mass (10.8 x 8.7 cm), suggesting a large subserous myoma or an ovarian tumor. Under the impression of pelvic mass, she underwent exploratory laparotomy. Primary ovarian sex-cord malignancy with cecum involvement was impressed by the primitive intraoperative frozen section report. Subsequently, an optimal cytoreductive operation with right hemicolectomy was performed. However, final histopathologic report was an extranodal multifocal BL. Although extranodal BL in ovaries is a rare condition, it should be noted in the differential diagnosis of pelvic gynecologic malignancies.


F-spondin negatively regulates dental follicle differentiation through the inhibition of TGF-β activity.
F-spondin is an extracellular matrix (ECM) protein that belongs to the thrombospondin type I repeat superfamily and is a negative regulator of bone mass. We have previously shown that f-spondin is specifically expressed in the dental follicle (DF), which gives rise to the periodontal ligament (PDL) during the tooth root formation stage. To investigate the molecular mechanism of PDL formation, we investigated the function of f-spondin in DF differentiation. The expression patterning of f-spondin in the developing tooth germ was compared with that of periodontal ligament-related genes, including runx2, type I collagen and periostin, by in situ hybridization analysis. To investigate the function of f-spondin during periodontal ligament formation, an f-spondin adenovirus was infected into the bell stage of the developing tooth germ, and the effect on dental differentiation was analyzed. F-spondin was specifically expressed in the DF of the developing tooth germ; by contrast, type I collagen, runx2 and periostin were expressed in the DF and in the alveolar bone. F-spondin-overexpresssing tooth germ exhibited a reduction in gene expression of periostin and type I collagen in the DF. By contrast, the knockdown of f-spondin in primary DF cells increased the expression of these genes. Treatment with recombinant f-spondin protein functionally inhibited periostin expression induced by transforming growth factor-β (TGF-β). Our data indicated that f-spondin inhibits the differentiation of DF cells into periodontal ligament cells by inhibiting TGF-β. These data suggested that f-spondin negatively regulates PDL differentiation which may play an important role in the immature phenotype of DF.


[Effect of 1,25-dihydroxyvitamin D3 on posterior transforaminal lumbar interbody fusion in patients with osteoporosis and lumbar disc degenerative disease].
To investigate the role of 1,25-dihydroxyvitamin D3 in the posterior transforaminal lumbar interbody fusion (TLIF) for patients with osteoporosis and lumbar degenerative disease. Between November 20ll and October 2012, 44 patients with osteoporosis and lumbar degenerative disease were treated with TLIF and the clinical data were retrospectively analyzed. The patients were divided into 2 groups based on the administration of 1,25-dihydroxyvitamin D3. After TLIF operation, 1,25-dihydroxyvitamin D3 was used in 21 patients (trial group), and was not used in 23 patients (control group). There was no significant difference in gender, age, etiology, affected segment, and disease duration between 2 groups (P > 0.05). Lumbar interbody fusion was observed by X-ray and thin-section CT scan reconstruction of lumbar spine according to Brantigan assessment system at 6 months after operation and last follow-up. Clinical outcome was evaluated by Oswestry disability index (ODI) before and after operation. The patients of 2 groups were followed up 12-27 months (mean, 14.5 months). No fixation loosening or breaking occurred during follow-up. ODI scores in both groups were significantly improved at 6 months after operation and last follow-up (P < 0.05) when compared with preoperative value. Although at preoperation there was no significant difference in ODI score between 2 groups (P > 0.05), ODI score of trial group was significantly lower than that of control group at 6 months after operation and last follow-up (P < 0.05). At 6 months after operation, the interbody fusion rate was 76.19% (16/21) in trial group and 43.48% (10/23) in control group, showing significant difference (χ2 = 3.60, P =0.03); at last follow-up, the fusion rate was 95.24% (20/21) in trial group and 65.22% (15/23) in control group, showing significant difference (χ2 = 4.38, P = 0.02). 1,25-dihydroxyvitamin D3 can improve the lumbar interbody fusion rate and general conditions in the patients with osteoporosis and lumbar degenerative disease.


Effects of electroporation on optically recorded transmembrane potential responses to high-intensity electrical shocks.
The outcome of defibrillation shocks is determined by the nonlinear transmembrane potential (DeltaVm) response induced by a strong external electrical field in cardiac cells. We investigated the contribution of electroporation to DeltaVm transients during high-intensity shocks using optical mapping. Rectangular and ramp stimuli (10-20 ms) of different polarities and intensities were applied to the rabbit heart epicardium during the plateau phase of the action potential (AP). DeltaVm were optically recorded under a custom 6-mm-diameter electrode using a voltage-sensitive dye. A gradual increase of cathodal and well as anodal stimulus strength was associated with 1) saturation and subsequent reduction of DeltaVm; 2) postshock diastolic resting potential (RP) elevation; and 3) postshock AP amplitude (APA) reduction. Weak stimuli induced a monotonic DeltaVm response and did not affect the RP level. Strong shocks produced a nonmonotonic DeltaVm response and caused RP elevation and a reduction of postshock APA. The maximum positive and maximum negative DeltaVm were recorded at 170 +/- 20 mA/cm2 for cathodal stimuli and at 240 +/- 30 mA/cm2 for anodal stimuli, respectively (means +/- SE, n = 8, P = 0.003). RP elevation reached 10% of APA at a stimulus strength of 320 +/- 40 mA/cm2 for both polarities. Strong ramp stimuli (20 ms, 600 mA/cm2) induced a nonmonotonic DeltaVm response, reaching the same largest positive and negative values as for rectangular shocks. The transition from monotonic to nonmonotonic morphology correlates with RP elevation and APA reduction, which is consistent with cell membrane electroporation. Strong shocks resulted in propidium iodide uptake, suggesting sarcolemma electroporation. In conclusion, electroporation is a likely explanation of the saturation and nonmonotonic nature of cellular responses reported for strong electric stimuli.


Utilization and Perception of Telemedicine among Orthopedic Surgeons.
Telemedicine has been a growing trend. Its use in the field of orthopedic surgery has its own unique facets. To determine the perception and assess the utilization of telemedicine the current study was conducted. This is a cross-sectional exploratory study conducted from January to April 2022 among 142 orthopedic surgeons across India who had previous experience of using telemedicine and were willing to participate in this study. The data was collected using a validated semi-structured questionnaire consisting of 44 multiple Choice questions, divided into 7 sections: experience in using telemedicine, technical aspects, patient selection, problems faced, benefits, current use, and opinions designed in English language. The data obtained from the responses were tabulated, analyzed and expressed in proportions. We found that nearly 80% of orthopedic surgeons believed that teleconsultation was most appropriate for follow up visits. The two most common issues faced were technical issues relating to poor video/audio/connectivity, and difficulty with regard to viewing of radiographs, MRI films etc. The major advantage was perceived to be easier access for patients, especially bed ridden/old patients. Our survey showed a significantly positive response toward telemedicine. Technical issues and lack of clinical examination were cited as the most common hindrances faced. Saving the time of the patient, and easier access to healthcare for old aged individuals, bed ridden patients and individuals in remote areas were the major perceived benefits.


The role of sevelamer in achieving the kidney disease outcomes quality initiative (K/DOQI) guidelines for hyperphosphatemia.
End-stage renal disease (ESRD) is a chronic health care problem associated with multiple co-morbidities and escalating costs. Disregulation of mineral metabolism (principally hyperphosphatemia and hypercalcemia) contributes to substantial morbidity and mortality. Accordingly, new and more-aggressive Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines from the National Kidney Foundation promote lower serum phosphorus (3.5-5.5 mg/dL), lower calcium (8.4-9.5 mg/dL), and lower calcium-phosphorus product (< 55 mg(2)/dL(2)) targets. Traditional calcium-based and metal-based phosphate binders are effective but are associated with side effects and toxicity that limit their use. Achieving rigorous K/DOQI goals demands higher therapeutic doses of phosphate binders and may require more-aggressive use of calcium-free and metal-free phosphate binders. Sevelamer hydrochloride is a calcium- and metal-free polymer that binds phosphate effectively without contributing to calcium load or metal accumulation. In the Treat-to-Goal trial, sevelamer-treated dialysis patients had less progression of coronary and aortic calcification than patients treated with calcium-based binders. This offers the potential promise of reducing cardiovascular morbidity and mortality. The 800-mg tablet (Renagel) increases the daily sevelamer dose while reducing the number of tablets required per meal. Nine of the 800-mg tablets per day (3 x 800-mg tablets tid with meals) of sevelamer monotherapy have been shown to achieve K/DOQI serum phosphorus and calcium-phosphorus product targets. In summary, this review of the current evidence-base concludes that the new, more-aggressive, K/DOQI goals limit the use of metal-based and calcium-based phosphate binders. Sevelamer offers the advantages of lowering serum phosphorus without the risks of calcium or metal accumulation - and offers the promise of slowing the progression of vascular calcification and potentially reducing the morbidity and mortality of hemodialysis patients.


Novel approach for evaluation of estrogenic and anti-estrogenic activities of genistein and daidzein using B16 melanoma cells and dendricity assay.
The effects of soy isoflavones, genistein and daidzein, which exhibit estrogenic, anti-estrogenic and/or tyrosine kinase inhibitory activity, on the dendritic morphology of B16 mouse melanoma cells were quantitatively evaluated and compared with those of 17 beta-estradiol (Est) and tyrphostin, a tyrosine kinase inhibitor. Dendricity was significantly stimulated in the order of Est >> genistein > daidzein = tyrphostin, but not by glycosides of genistein and daidzein. In competition experiments, Est counteracted the stimulatory activity of genistein and daidzein, but enhanced the activity of tyrphostin additively, suggesting that genistein and daidzein agonized Est. In addition, when the concentration ratios of genistein/Est and daidzein/Est were higher than 5000 and 50,000, respectively, genistein and daidzein agonized Est. In contrast, when the ratio of daidzein/Est was lower than 500, daidzein antagonized Est. Furthermore, genistein and daidzein competed with each other in stimulatory activity. These observations suggest that: 1) dendricity is stimulated by agonists (genistein and daidzein) of Est and tyrosine kinase inhibitors (genistein and tyrphostin), 2) the concentration ratio of isoflavone aglycone/Est is very important as one regulatory factor for estrogenic and/or anti-estrogenic activity, and 3) daidzein antagonizes not only Est but also genistein. It is concluded that a quantitative and simple dendricity assay using B16 mouse melanoma cells is available to evaluate estrogenic and anti-estrogenic activity in vitro.


[Optimizing conditions for the expression of human beta defensin 3 and des-pGlu1-Brazzein in Escherichia coli and analysis of their activity].
The inductive conditions for the flask-shaking of E.coli BL21-pET-hBD3-Bra had been optimized, at the same time, the expressed protein had been purified and analyzed. The effect of three factors which were IPTG concentration, induction time and temperature on growth of strain and on the yield of hBD3-Bra was analyzed in detail. The result indicated that the concentration of IPTG had little effect on the growth and the expression of target protein between 0.2-1 mmol/L, Biomass would be improved as time passed, but the target protein didn't increase obviously as the same time, temperature was the most important factor, the expressed level of hBD3-Bra, as high as about 35% of total cell protein, could be gained when strain was induced by IPTG under 30 degrees C. Further analysis showed the best temperature for growth was 30 degrees C-32 degrees C and for expression protein was 30 degrees C.The purified hBD3-Bra has a weak antimicrobial activity, but is 200 times sweeter than that of sucrose. After digested by thrombin and purified by affinity column, the natural des-pGlul-Brazzein also has 600-time sweetness of sucrose, and the recombinant hBD3 has a high antimicrobial activity again E. coli and S. aureus.


Outcomes of nighttime refusal of admission to the intensive care unit: The role of the intensivist in triage.
To compare outcomes of patients refused medical intensive care unit (MICU) admission overnight to those refused during the day and to examine the impact of the intensivist in triage. Retrospective, observational study of patients refused MICU admission at an urban university hospital. Of 294 patients, 186 (63.3%) were refused admission overnight compared to 108 (36.7%) refused during the day. Severity-of-illness by the Mortality Probability Model was similar between the two groups (P=.20). Daytime triage refusals were more likely to be staffed by an intensivist (P=.01). After risk-adjustment, daytime refusals had a lower odds of subsequent ICU admission (OR 0.46, 95% CI 0.22-0.95, P=.04) than patients triaged at night. There was no evidence for interaction between time of triage and intensivist staffing of the patient (P=.99). Patients refused MICU admission overnight are more likely to be later admitted to an ICU than patients refused during the day. However, the mechanism for this observation does not appear to depend on the intensivist's direct evaluation of the patient. Further investigation into the clinician-specific effects of ICU triage and identification of potentially modifiable hospital triage practices will help to improve both ICU utilization and patient safety.


Teaching systematic, reproducible model development using synthetic biology.
We present an educational unit to teach computational modeling, a vital part of chemical engineering curricula, through the lens of synthetic biology. Lectures, code, and homework questions provide conceptual and practical introductions to each computational method involved in the model development process, along with perspectives on how methods can be iterated upon to arrive at a final model. Ultimately, this content can be applied broadly to address questions in synthetic biology and classical chemical engineering.


Anti-DNA antibody synthesis after bone marrow transplantation: implications for IgG subclass restrictivity and pathogenicity of autoantibodies.
Two patients developed antinuclear antibodies (ANA) including antibodies directed against double-stranded DNA (dsDNA) after bone marrow transplantation. In one of the patients very high levels of IgM, IgG as well as IgA anti-dsDNA were found during 6 months in the absence of symptoms of systemic lupus erythematosus (SLE). The other patient made IgM anti-dsDNA antibodies for a period of more than 3 years, also in the absence of SLE symptoms. The ANA were restricted to the IgG1 and IgG3 isotypes as is the case in SLE but did not express idiotypes commonly found in this autoimmune disease. The occurrence of these antibodies may reflect a non-antigen induced expansion of the existing donor B-lymphocyte repertoire.


AgeLine: a database of social gerontology literature.
AgeLine, an EBSCO host database, focuses on literature on topics relating to people over the age of 50. AgeLine is geared to professionals in aging-related fields, such as health care professionals, social workers, and caregivers, as well as consumers. This column includes a sample search and a discussion of additional AgeLine features.


Differences and discriminatory power of water polo game-related statistics in men in international championships and their relationship with the phase of the competition.
The aims of this study were (a) to compare water polo game-related statistics by context (winning and losing teams) and phase (preliminary, classification, and semifinal/bronze medal/gold medal), and (b) identify characteristics that discriminate performances for each phase. The game-related statistics of the 230 men's matches played in World Championships (2007, 2009, and 2011) and European Championships (2008 and 2010) were analyzed. Differences between contexts (winning or losing teams) in each phase (preliminary, classification, and semifinal/bronze medal/gold medal) were determined using the chi-squared statistic, also calculating the effect sizes of the differences. A discriminant analysis was then performed after the sample-splitting method according to context (winning and losing teams) in each of the 3 phases. It was found that the game-related statistics differentiate the winning from the losing teams in each phase of an international championship. The differentiating variables are both offensive and defensive, including action shots, sprints, goalkeeper-blocked shots, and goalkeeper-blocked action shots. However, the number of discriminatory variables decreases as the phase becomes more demanding and the teams become more equally matched. The discriminant analysis showed the game-related statistics to discriminate performance in all phases (preliminary, classificatory, and semifinal/bronze medal/gold medal phase) with high percentages (91, 90, and 73%, respectively). Again, the model selected both defensive and offensive variables.


Frequency of polymorphisms of genes coding for HIV-1 co-receptors CCR5 and CCR2 in a Brazilian population.
Entry of human immunodeficiency type 1 virus (HIV-1) into target cells requires both CD(4)and one of the chemokine receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 and CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. A 32-nucleotide deletion (D32) within the b-chemokine receptor 5 gene (CCR5) has been described in subjects who remain uninfected despite extensive exposition to HIV-1. The heterozygous genotype delays disease progression. This allele is common among Caucasians, but has not been found in people of African or Asian ancestry. A more common transition involving a valine to isoleucine switch in transmembrane domain I of CCR2B (64I), with unknown functional consequences, was found to delay disease progression but not to reduce infection risk. As the Brazilian population consists of a mixture of several ethnic groups, we decided to examine the genotype frequency of these polymorphisms in this country. There were 11.5% CCR5 heterozygotes among the HIV-1 infected population and 12.5% among uninfected individuals, similar to data from North America and Western Europe. The prevalence of CCR2-64I homozygotes and heterozygotes was 0.06 and 15.2%, respectively, also similar to what is known for North America and Western Europe.


Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.
Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.


Body size, reproductive behavior, and fertility in three genetic lines of Japanese quail.
The influences of body size on early locomotor activity, intermale aggression, mating behavior, fertility, and hatchability were studied in three lines of Japanese quail. Lines P and C originated from the same base population with P selected for high 28-day body weight and C maintained as a randombred population. Line S was a randombred line unrelated to P and C. Line P quail were larger than both C and S quail, which were similar in size and had proportionally larger cloacal glands than those from the P line. The P and S males were more aggressive than C males. Although there was no difference among the three lines for number of attempted matings, C and S males completed more matings and had better mating efficiency and fertility than P males. The P females received more attempted matings than C and S females, but S females completed more matings, resulting in higher mating efficiency. Fertility tended to be lower in P females, while hatchability of fertile eggs was similar across all lines. The effect of body size on reproductive performance is discussed in the context of genetic homeostasis.


Exploring molecular markers and drug candidates for colorectal cancer through comprehensive bioinformatics analysis.
Colorectal cancer (CRC) often has a poor prognosis and identifying useful and novel agents for treating CRC is urgently required. This study aimed to examine molecular markers associated with CRC prognosis and to identify potential drug candidates. The differentially expressed genes (DEGs) of CRC in TCGA were identified. The genes associated with CRC, summarized from NCBI-gene, OMIM, and the DEGs, were used to construct a co-expression network by WGCNA. Moreover, the co-expression genes from modules of interest were used to carry out functional enrichment. A total of 2742 DEGs, including 1674 upregulated and 1068 downregulated genes, were identified. Thirteen co-expression modules were constructed with WGCNA. Brown and blue co-expression modules with significant differences in disease phenotype were found. Functional enrichment analysis showed that genes in the brown module were mainly related to cell cycle, cell proliferation, DNA replication, and RNA transport. The genes in the blue module were mainly associated with fatty acid degradation, sulfur metabolism, PPAR signaling pathway and bile secretion. In addition, both the genes in brown and blue were associated with tumor staging. Some prognostic markers and candidate small molecules drugs for CRC treatment were identified. In conclusion, we revealed molecular biomarker profiles in CRC by systematic bioinformatics analysis, constructed regulatory networks of mRNA, ncRNA and transcriptional regulators (TFs), and identified potential drugs targeting hub proteins and TFs.


Predictive modeling of oocyte maternal mRNA features of five mammalian species reveals potential shared and species-restricted regulators during maturation.
Oocyte maturation is accompanied by changes in abundances of thousands of mRNAs, many degraded and many preferentially stabilized. mRNA stability can be regulated by diverse features including GC content, codon bias, and motifs within the 3' untranslated region (UTR) interacting with RNA binding proteins (RBPs) and miRNAs. Many studies identified factors participating in mRNA splicing, bulk mRNA storage and translational recruitment in mammalian oocytes, but the roles of potentially hundreds of expressed factors, how they regulate cohorts of thousands of mRNAs, and to what extent their functions are conserved across species has not been determined. We performed an extensive in-silico cross-species analysis of features associated with mRNAs of different stability classes during oocyte maturation (stable, moderately degraded, and highly-degraded) for five mammalian species. Using publicly available RNA sequencing data for GV and MII oocyte transcriptomes, we determined that 3'UTR length and synonymous codon usage are positively associated with stability whilst greater GC content is negatively associated with stability. By applying machine learning and feature selection strategies, we identified RBPs and miRNAs that are predictive of mRNA stability, including some across multiple species and others more species-restricted. The results provide new insight into the mechanisms regulating maternal mRNA stabilization or degradation.


Structure-activity relationships of 33 carboxamides as toxicants against female Aedes aegypti (Diptera: Culicidae).
Aedes aegypti L. is the primary vector of dengue and yellow fever viruses, and use of aerosolized insecticides is one of the primary ways to control this medically important mosquito. However, few new insecticides have been developed for mosquito control in recent years. As a part of our effort to search for new insecticides to control mosquitoes, toxicities of 33 carboxamides were evaluated against female A. aegypti by topical application. This group included nine different categories of compounds, namely benzamides, phenyl-propenamides, propanamides, butanamides, butenamides, pentanamides, pentenamides, hexanamides, and hexenamides, that exhibited varying levels of toxicity against this mosquito species. The most toxic compound tested was hexahydro-1-(1-oxohexyl)-1H-azepine, with a 24-h LD50 value of 0.4 microg per mosquito, whereas the most toxic compound at the LD95 level was N-ethyl-2-methyl-N-phenyl-benzamide (1.82 microg per mosquito). The least toxic compound was N,N-bis (2-methylpropyl)-3-phenyl-2-propenamide, with LD50 and LD95 values of 15.66 and 72.07 microg per mosquito, respectively. Results from this initial study may prove useful in guiding further carboxamide modifications for the development of potential new insecticides.


Interferon-gamma: pleiotropic effects on a rat pancreatic beta cell line.
We have recently shown that interferon-gamma (IFN-gamma) markedly upregulates the expression of the class I major histocompatibility proteins on pancreatic beta cells and have therefore postulated that interferon-gamma may enhance cytotoxic lymphocyte-mediated beta cell damage in insulin-dependent diabetes mellitus. To further explore the interaction between interferon-gamma and the pancreatic beta cell we have used the RIN-m5F insulinoma line to define the effects of interferon-gamma on major histocompatibility protein expression, (pro)insulin and protein synthesis and cell growth. Interferon-gamma induced a dose-dependent increase in the expression of the class I major histocompatibility proteins on the RIN-m5F cells, the maximal increase (10-fold) being seen at an interferon-gamma concentration of 1 U/ml. The induction of class I proteins by interferon-gamma was nearly completely abolished by cycloheximide. Expression of class II (Ia) proteins was not detected either in the presence or absence of interferon-gamma. (Pro)insulin and protein synthesis were decreased by 60% and 40%, respectively, in RIN-m5F cells cultured with interferon-gamma (10 U/ml). Furthermore, the growth of RIN-m5F cells was significantly inhibited, and corresponding changes in cell morphology were evident, after 3 days of exposure to interferon-gamma (10 U/ml). These findings indicate that, in addition to its potential role in amplifying cytotoxic T cell activity against the pancreatic beta cell, IFN-gamma may also directly inhibit beta cell function and growth. Several mechanisms could therefore account for an ability of IFN-gamma to compromise beta cell function and contribute to the pathogenesis of insulin-dependent diabetes.


Managing chronic oedema: a collaborative community approach.
Chronic oedema affects over 100 000 people in the UK and is regularly treated by different health care professionals, most commonly community nurses. The effect of chronic oedema on patients can be both physical and emotional and is a huge financial burden on the NHS. Collaborative working between lymphoedema services and community nurses is outlined in this article, highlighting potential benefits to patient care and substantial cost savings. Modified lymphoedema management strategies to treat chronic oedema effectively are identified with the emphasis on joint packages of care and patient goal setting. The role of health care professionals working collaboratively and empowering patients are also discussed in a case study.


Respiratory symptoms due to active and passive smoking in junior secondary school students in Hong Kong.
Evidence on respiratory symptoms due to smoking and passive smoking in children is mainly derived from studies in Western countries. Evidence from the East was required to support stronger tobacco control policy in Asia. This study aimed to analyse the relationship between respiratory symptoms and smoking status in junior secondary students and between respiratory symptoms and family smoking in never-smoking students. In a cross-sectional survey in 1994, anonymous questionnaires were administered to a two-stage cluster probability sample of 6304 students, aged mostly 12-15 years, from 172 classes of 61 schools in Hong Kong. Significant linear trends were found between smoking and the prevalence of throat and nose problems, cough and phlegm, and wheezing. The odds ratio (OR), after adjustment for age, gender, area of residence, type of housing and correlation within schools and classes (cluster effects), for smoking at least weekly ranged from 1.35 to 4.84. In never-smoking children, significant trends were found between the number of smokers living with the children and throat and nose problems, cough and phlegm, and recent wheezing. The adjusted OR and 95% confidence interval (CI) for any cough or phlegm symptoms was 1.19 (95% CI: 1.01-1.47) for one smoking household member, 1.38 (95% CI: 1.07-1.79) for two and 1.85 (95% CI: 1.19-2.85) for three (P for trend <0.001). Increased OR were found for father and mother smoking. This study provides strong evidence that both active and passive smoking can cause respiratory ill health in Chinese children in Hong Kong. Urgent measures are needed to protect children from the health hazards of active and passive smoking in Asia.


Dense granule protein 3 of Toxoplasma gondii plays a crucial role in the capability of the tissue cysts of the parasite to persist in the presence of anti-cyst CD8+ T cells during the chronic stage of infection.
Toxoplasma gondii establishes chronic infection by forming tissue cysts, and this chronic infection is one of the most common parasitic infections in humans. Our recent studies revealed that whereas CD8+ T cells of genetically resistant BALB/c mice have the capability to remove the tissue cysts of the parasite through their perforin-mediated activities, small portions of the cysts are capable of persisting in the presence of the anti-cyst CD8+ T cells. It is currently unknown how those small portions of the cysts resist or escape the T-cell immunity and persist in the hosts. In the present study, we discovered that the cysts, which persisted in the presence of the perforin-mediated CD8+ T-cell immunity, have significantly greater mRNA levels for four dense granule proteins, GRA1, GRA2, GRA3, and GRA7, and one rhoptry protein, ROP35, than the total population of the cysts present in the absence of the T cells. In addition, increased levels of mRNA for GRA1, GRA3, and ROP35 in the cysts significantly correlated with their successful persistence through the condition in which greater degrees of reduction of the cyst burden occurred through anti-cyst CD8+ T cells. In addition, GRA3-deficient T. gondii displayed significantly enhanced elimination of the cysts by anti-cyst CD8+ T cells when compared to the wild-type parasite. These results indicate that GRA3 is a key molecule that mediates in the capability of T. gondii cysts to persist by resisting or evading the anti-cyst activity of CD8+ T cells during the later stage of infection.


[Ultrasound diagnosis of the phoniatric performance of laryngectomized patients].
Sonography of the pharyngo-oesophageal segment and pseudoglottis was performed in 10 laryngectomised patients with varying oesophageal voice development. the post-laryngectomal telephone comprehension test served as a yardstick for assessing the quality of the oesophageal voice. Sonographic B and M mode techniques in transverse section provided a good overall assessment of the function of the pharyngo-oesophageal segment. Likewise, a clear picture of the pseudoglottis can be obtained and rapid motoric effects in phonation easily seen. Each vocal demonstrates a typical sonographic pattern in the M-mode. There is a clear correlation between increasing quality of the oesophageal voice and differentiation of echo amplitude. Our experience to date recommends the use of sonography of the pharyngo-oesophageal segment and pseudoglottis in laryngectomised patients for the phoniatric assessment of oesophageal voice functioning.


Detection of signs of disease in external photographs of the eyes via deep learning.
Retinal fundus photographs can be used to detect a range of retinal conditions. Here we show that deep-learning models trained instead on external photographs of the eyes can be used to detect diabetic retinopathy (DR), diabetic macular oedema and poor blood glucose control. We developed the models using eye photographs from 145,832 patients with diabetes from 301 DR screening sites and evaluated the models on four tasks and four validation datasets with a total of 48,644 patients from 198 additional screening sites. For all four tasks, the predictive performance of the deep-learning models was significantly higher than the performance of logistic regression models using self-reported demographic and medical history data, and the predictions generalized to patients with dilated pupils, to patients from a different DR screening programme and to a general eye care programme that included diabetics and non-diabetics. We also explored the use of the deep-learning models for the detection of elevated lipid levels. The utility of external eye photographs for the diagnosis and management of diseases should be further validated with images from different cameras and patient populations.


Chromosome-level genome assembly of Japanese chestnut (Castanea crenata Sieb. et Zucc.) reveals conserved chromosomal segments in woody rosids.
Japanese chestnut (Castanea crenata Sieb. et Zucc.), unlike other Castanea species, is resistant to most diseases and wasps. However, genomic data of Japanese chestnut that could be used to determine its biotic stress resistance mechanisms have not been reported to date. In this study, we employed long-read sequencing and genetic mapping to generate genome sequences of Japanese chestnut at the chromosome level. Long reads (47.7 Gb; 71.6× genome coverage) were assembled into 781 contigs, with a total length of 721.2 Mb and a contig N50 length of 1.6 Mb. Genome sequences were anchored to the chestnut genetic map, comprising 14,973 single nucleotide polymorphisms (SNPs) and covering 1,807.8 cM map distance, to establish a chromosome-level genome assembly (683.8 Mb), with 69,980 potential protein-encoding genes and 425.5 Mb repetitive sequences. Furthermore, comparative genome structure analysis revealed that Japanese chestnut shares conserved chromosomal segments with woody plants, but not with herbaceous plants, of rosids. Overall, the genome sequence data of Japanese chestnut generated in this study is expected to enhance not only its genetics and genomics but also the evolutionary genomics of woody rosids.


Hetero-trans-β-Glucanase Produces Cellulose-Xyloglucan Covalent Bonds in the Cell Walls of Structural Plant Tissues and Is Stimulated by Expansin.
Current cell-wall models assume no covalent bonding between cellulose and hemicelluloses such as xyloglucan or mixed-linkage β-d-glucan (MLG). However, Equisetum hetero-trans-β-glucanase (HTG) grafts cellulose onto xyloglucan oligosaccharides (XGOs) - and, we now show, xyloglucan polysaccharide - in vitro, thus exhibiting CXE (cellulose:xyloglucan endotransglucosylase) activity. In addition, HTG also catalyzes MLG-to-XGO bonding (MXE activity). In this study, we explored the CXE action of HTG in native plant cell walls and tested whether expansin exposes cellulose to HTG by disrupting hydrogen bonds. To quantify and visualize CXE and MXE action, we assayed the sequential release of HTG products from cell walls pre-labeled with substrate mimics. We demonstrated covalent cellulose-xyloglucan bonding in plant cell walls and showed that CXE and MXE action was up to 15% and 60% of total transglucanase action, respectively, and peaked in aging, strengthening tissues: CXE in xylem and cells bordering intercellular canals and MXE in sclerenchyma. Recombinant bacterial expansin (EXLX1) strongly augmented CXE activity in vitro. CXE and MXE action in living Equisetum structural tissues potentially strengthens stems, while expansin might augment the HTG-catalyzed CXE reaction, thereby allowing efficient CXE action in muro. Our methods will enable surveys for comparable reactions throughout the plant kingdom. Furthermore, engineering similar hetero-polymer formation into angiosperm crop plants may improve certain agronomic traits such as lodging tolerance.


The effectiveness of different aerobic exercises to improve pain intensity and disability in chronic low back pain patients: a systematic review.
Background: Physical activity, including aerobic exercise, is highly recommended for chronic low back pain (CLBP) patients to improve pain intensity and functional disability. Objectives: To assess the effectiveness of different aerobic exercises to reduce pain intensity and functional disability in patients with CLBP. Methods: A computer-aided search was performed to find Randomised Controlled Trials (RCTs) that evaluated the effectiveness of different aerobic exercises in CLBP. Articles published between January 2007 to December 2020 were included in the review. Quality assessment using the PEDro scale, extraction of relevant information, and evaluation of outcomes were done by two reviewers independently. Results: A total of 17 studies were included that involved 1146 participants. Outcomes suggested that aerobic exercise combined with other interventions was more effective than aerobic exercise alone. Aerobic exercise with higher frequency (≥ 5 days/week) and longer duration (≥ 12 weeks) were effective to gain clinically significant (≥ 30%) improvements. Environment and using pedometer did not seem to influence the outcomes. Conclusions: Pain intensity and functional disability in CLBP patients can be minimized by prescribing aerobic exercise. However, to get better improvements, aerobic exercise should be done in combination with other interventions and at optimum frequency and duration. Further studies should emphasize examining the optimal doses and duration of different aerobic exercises.


Domain II of the translation elongation factor eEF1A is required for Gcn2 kinase inhibition.
The signalling pathway governing general control nonderepressible (Gcn)2 kinase allows cells to cope with amino acid shortage. Under starvation, Gcn2 phosphorylates the translation initiation factor eukaryotic translation initiation factor (eIF)2α, triggering downstream events that ultimately allow cells to cope with starvation. Under nutrient-replete conditions, the translation elongation factor eEF1A binds Gcn2 to contribute to keeping Gcn2 inactive. Here, we aimed to map the regions in eEF1A involved in binding and/or regulating Gcn2. We find that eEF1A amino acids 1-221 and 222-315, containing most of domains I and II, respectively, bind Gcn2 in vitro. Overexpression of eEF1A lacking or containing domain III impairs eIF2α phosphorylation. While the latter reduces growth under starvation similarly to eEF1A lacking domain I, the former enhances growth in a Gcn2-dependent manner. Our studies suggest that domain II is required for Gcn2 inhibition and that eEF1A lacking domain III mainly affects the Gcn2 response pathway downstream of Gcn2.


Prevalence and association of premenstrual syndrome and premenstrual dysphoric disorder with academic performance among female university students.
Premenstrual dysphoric disorder (PMDD) is particularly a female psychological disorder that has consequences on female students' behavior, cognitive abilities, mental health status, and academic performance. To examine the prevalence of premenstrual syndrome (PMS) and PMDD, and their relationship with academic performance among female university students in Jordan. Prospective-correlational design was employed among 858 university students. Data collected in regards to daily record of signs of PMDD and PMS, academic motivation, and student's involvement. Prevalence of PMS was 92.3% and that of PMDD was 7.7%. There were significant differences in self-determination levels between students with PMS and those with PMDD. PMDD symptoms have a negative impact on female students' academic performance; thus, mental health professionals have a major role in determining factors that buffer severity of PMDD among females.


Chronic disease management in patients with intellectual disabilities: a matched study in Dutch general practice.
Disease management programmes (DMPs) aim to deliver standardised, high- quality care to patients with chronic diseases. Although chronic diseases are common among people with intellectual disabilities (ID), this approach may be suboptimal for meeting their care needs. To examine differences between patients with and without ID who have a chronic illness in DMP enrolment and disease monitoring in Dutch general practice. Observational study utilising the Nivel Primary Care Database (2015-2018) comparing patients with ID and cardiovascular disease, diabetes mellitus, or chronic obstructive pulmonary disease (COPD) with matched (1:5) controls with these conditions but without ID. Using conditional logistic regression, enrolment in DMP per chronic disease was examined and differences tested between groups in the frequencies of consultations, medication prescriptions, and routine examinations. A total of 2653 patients with chronic illness with ID were matched with 13 265 controls without ID. Patients with both diabetes mellitus and ID were more likely than controls to be enrolled in DMP (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.64). Independent of DMP enrolment, patients with chronic illness with ID were more likely than controls to have frequent consultations. Patients with both diabetes mellitus and ID and patients with both COPD and ID who were not enrolled in DMPs had more medication prescriptions than non-enrolled patients with diabetes or COPD but without ID (OR = 1.46, 95% CI = 1.10 to 1.95; OR = 1.28, 95% CI = 0.99 to 1.66, respectively). Most patients with ID and their controls enrolled in DMPs received routine examinations at similar frequencies. Although DMPs do not specifically address the needs of patients with both chronic illness and ID, these patients do not seem underserved in the management of chronic diseases in terms of consultation, medication, and tests.


Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients.
To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer. Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned. The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group. XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.


Reduction of sulfenic acids by ascorbate in proteins, connecting thiol-dependent to alternative redox pathways.
Sulfenic acids are the primary product of thiol oxidation by hydrogen peroxide and other oxidants. Several aspects of sulfenic acid formation through thiol oxidation were established recently. In contrast, the reduction of sulfenic acids is still scarcely investigated. Here, we characterized the kinetics of the reduction of sulfenic acids by ascorbate in several proteins. Initially, we described the crystal structure of our model protein (Tsa2-C170S). There are other Tsa2 structures in distinct redox states in public databases and all of them are decamers, with the peroxidatic cysteine very accessible to reductants, convenient features to investigate kinetics. We determined that the reaction between Tsa2-C170S-Cys-SOH and ascorbate proceeded with a rate constant of 1.40 ± 0.08 × 103 M-1 s-1 through a competition assay developed here, employing 2,6-dichlorophenol-indophenol (DCPIP). A series of peroxiredoxin enzymes (Prx6 sub family) were also analyzed by this competition assay and we observed that the reduction of sulfenic acids by ascorbate was in the 0.4-2.2 × 103 M-1 s-1 range. We also evaluated the same reaction on glyceraldehyde 3-phosphate dehydrogenase and papain, as the reduction of their sulfenic acids by ascorbate were reported previously. Once again, the rate constants are in the 0.4-2.2 × 103 M-1 s-1 range. We also analyzed the reduction of Tsa2-C170S-SOH by ascorbate by a second, independent method, following hydrogen peroxide reduction through a specific electrode (ISO-HPO-2, World Precision Instruments) and employing a bi-substrate, steady state approach. The kcat/KMAsc was 7.4 ± 0.07 × 103 M-1 s-1, which was in the same order of magnitude as the value obtained by the DCPIP competition assay. In conclusion, our data indicates that reduction of sulfenic acid in various proteins proceed at moderate rate and probably this reaction is more relevant in biological systems where ascorbate concentrations are high.


Application of stopped-flow kinetics methods to investigate the mechanism of action of a DNA repair protein.
Transient kinetic analysis is indispensable for understanding the workings of biological macromolecules, since this approach yields mechanistic information including active site concentrations and intrinsic rate constants that govern macromolecular function. In case of enzymes, for example, transient or pre-steady state measurements identify and characterize individual events in the reaction pathway, whereas steady state measurements only yield overall catalytic efficiency and specificity. Individual events such as protein-protein or protein-ligand interactions and rate-limiting conformational changes often occur in the millisecond timescale, and can be measured directly by stopped-flow and chemical-quench flow methods. Given an optical signal such as fluorescence, stopped-flow serves as a powerful and accessible tool for monitoring reaction progress from substrate binding to product release and catalytic turnover(1,2). Here, we report application of stopped-flow kinetics to probe the mechanism of action of Msh2-Msh6, a eukaryotic DNA repair protein that recognizes base-pair mismatches and insertion/deletion loops in DNA and signals mismatch repair (MMR)(3-5). In doing so, Msh2-Msh6 increases the accuracy of DNA replication by three orders of magnitude (error frequency decreases from approximately 10(-6) to 10(-9) bases), and thus helps preserve genomic integrity. Not surprisingly, defective human Msh2-Msh6 function is associated with hereditary non-polyposis colon cancer and other sporadic cancers(6-8). In order to understand the mechanism of action of this critical DNA metabolic protein, we are probing the dynamics of Msh2-Msh6 interaction with mismatched DNA as well as the ATPase activity that fuels its actions in MMR. DNA binding is measured by rapidly mixing Msh2-Msh6 with DNA containing a 2-aminopurine (2-Ap) fluorophore adjacent to a G:T mismatch and monitoring the resulting increase in 2-aminopurine fluorescence in real time. DNA dissociation is measured by mixing pre-formed Msh2-Msh6 G:T(2-Ap) mismatch complex with unlabeled trap DNA and monitoring decrease in fluorescence over time(9). Pre-steady state ATPase kinetics are measured by the change in fluorescence of 7-diethylamino-3-((((2-maleimidyl)ethyl)amino)carbonyl) coumarin)-labeled Phosphate Binding Protein (MDCC-PBP) on binding phosphate (Pi) released by Msh2-Msh6 following ATP hydrolysis(9,10). The data reveal rapid binding of Msh2-Msh6 to a G:T mismatch and formation of a long-lived Msh2-Msh6 G:T complex, which in turn results in suppression of ATP hydrolysis and stabilization of the protein in an ATP-bound form. The reaction kinetics provide clear support for the hypothesis that ATP-bound Msh2-Msh6 signals DNA repair on binding a mismatched base pair in the double helix. F


Clinical trial of a potent non-halogenated topical steroid, Budesonide.
In a double-blind, randomized multi-centre study, 116 patients with psoriasis have been treated for 1-3 weeks with budesonide ointment (Preferid, Draco/Tika; a subsidiary of AB ASTRA), a new non-halogenated topical steroid. In a series of 11 patients a 0.025% budesonide ointment was significantly superior to placebo. In a second series, of 54 patients, a 0.025% fluocinolone acetonide ointment (Synalar, ICI). In a third series, of 51 patients, a 0.010% budesonide ointment was compared with 0.025% fluocinolone acetonide ointment. No statistically significant difference between these two preparations was found to exist. No adverse reactions were observed.


A transcription factor collective defines the HSN serotonergic neuron regulatory landscape.
Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years.


Frequency of autoantibodies in normal children.
Very few data have been reported on the frequency of autoantibodies (AAs) in normal children. In the present study we investigated the frequency of 14 AAs in a total of 268 apparently normal children (151 boys and 117 girls; age range, 1 month to 14 years). Forty-one children (22 boys and 19 girls) were positive for at least one AA, usually in a low titer; two children were positive for two AAs. None of these children had a personal or family history of autoimmune diseases. The percentage of children positive for each AA was as follows: antinuclear, 3%; anti-smooth muscle, 2.6%; antireticulin, 2.6%; antimitochondrial, 1.1%; rheumatoid factor, 0.6%; antiribosomal, 0.4%; anti-gastric parietal cells, 5.2%; and anti-thyroid microsomal, 1.3%. Anti-double-stranded DNA, anti-intestinal epithelial cells, antiliver and antikidney microsomal, antithyroglobulin, anti-islet cells, and complement-fixing anti-islet cell antibodies were not detected in any serum. Fifteen of the 41 positive children were checked for the presence of AAs two years later; six (40%) were still positive, always for the same AA, without major differences in titer. Our results suggest that the overall frequency of AAs in apparently healthy children is quite similar to that reported in young adults; this AA positivity seems most often to represent a transient phenomenon.


[Leptin during pregnancy].
Leptin, the protein encoded by the Ob gene in the adipose cell, is produced by the placenta during pregnancy. This review describes recent findings regarding the putative functions of leptin during pregnancy. and methods. We searched the literature consulting Medline database. Placental leptin production makes a substantial contribution to maternal circulating levels during pregnancy. Leptin has been detected in fetal plasma as early as week 18 of gestation, and umbilical leptin concentrations are closely related to birth weight. This has led to the hypothesis that fetal fat mass mainly determines fetal circulating leptin. Placental leptin production is increased in choriocarcinoma, preeclampsia and type 1 diabetes. Estrogens, hypoxia and insulin have been suggested as positive regulators of placental leptin production. Maternal leptinemia might act as a sensor of energy balance during pregnancy. The presence of both leptin and leptin receptors in the placenta suggests that leptin can act by autocrine or endocrine pathways in the human placenta. The roles of fetal leptin and consequences of increased placental leptin production in pathological pregnancies have yet to be elucidated.


Development of a customised data management system for a COVID-19-adapted colorectal cancer pathway.
A customised data management system was required for a rapidly implemented COVID-19-adapted colorectal cancer pathway in order to mitigate the risks of delayed and missed diagnoses during the pandemic. We assessed its performance and robustness. A system was developed using Microsoft Excel (2007) to retain the spreadsheets' intuitiveness of direct data entry. Visual Basic for Applications (VBA) was used to construct a user-friendly interface to enhance efficiency of data entry and segregate the data for operational tasks. Large data segregation was possible using VBA macros. Data validation and conditional formatting minimised data entry errors. Computation by the COUNT function facilitated live data monitoring. It is possible to rapidly implement a makeshift database system with clinicians' regular input. Large-volume data management using a spreadsheet system is possible with appropriate data definition and VBA-programmed data segregation. The described concept is applicable to any data management system construction requiring speed and flexibility in a resource-limited situation.


Cephalometric measurments of a Pakistani adult sample according to Jarabak's analysis.
To establish cephalometric norms of Pakistani adults according to Jarabak's analysis and to evaluate whether a significant difference exists between Pakistani measurements and Jarabak's norms. A prospective cross-sectional study, was carried out at the Department of Orthodontics Dr. Ishratul Ebad Institute Of Oral Heath Sciences/Sindh Dental Hospital, Karachi from July to September 2012. Standardized lateral cephalometric radiographs were taken of 50 selected Pakistanis within age range 18-23 years having normal occlusion. The database was developed in SPSS 12.0 for Windows. A descriptive analysis and independent Student's test was used. A comparison of the angular and linear measurements according to the Jarabak's analysis in the Pakistani and Caucasian population describe that the Pakistani males had all of their angular as well as linear measurements significantly different then the Caucasian namely the saddle angle, gonial angle, articular angle, upper gonial angle and lower gonial angle (p < 0.0001) and the anterior cranial base, posterior cranial base, ramus height, anterior facial height, posterior facial height and mandibular corpus (p < 0.05). Pakistani males and females demonstrated a significant difference in saddle angle, gonial angle, articular angle, upper gonial angle and lower gonial angle (p < 0.0001) as compared to the Caucasian norms. Pakistani females also had a difference in the upper gonial angle and lower gonial angle (p < 0.0001) and the anterior cranial base, posterior cranial base, ramus height, anterior facial height, posterior facial height and mandibular corpus measurements.


Facile synthesis of hydroxy-modified MOF-5 for improving the adsorption capacity of hydrogen by lithium doping.
A facile synthesis of partially hydroxy-modified MOF-5 and its improved H2-adsorption capacity by lithium doping are reported. The reaction of Zn(NO3)2·6H2O with a mixture of terephthalic acid (H2BDC) and 2-hydroxyterephthalic acid (H2BDC-OH) in DMF gave hydroxy-modified MOF-5 (MOF-5-OH-x), in which the molar fraction (x) of BDC-OH(2-) was up to 0.54 of the whole ligand. The MOF-5-OH-x frameworks had high BET surface areas (about 3300 m(2) g(-1)), which were comparable to that of MOF-5. We suggest that the MOF-5-OH-x frameworks are formed by the secondary growth of BDC(2-)-rich MOF-5 seed crystals, which are nucleated during the early stage of the reaction. Subsequent Li doping into MOF-5-OH-x results in increased H2 uptake at 77 K and 0.1 MPa from 1.23 to 1.39 wt.% and an increased isosteric heat of H2 adsorption from 5.1-4.2 kJ mol(-1) to 5.5-4.4 kJ mol(-1).


A Smartphone-Based Automatic Measurement Method for Colorimetric pH Detection Using a Color Adaptation Algorithm.
This paper proposes a smartphone-based colorimetric pH detection method using a color adaptation algorithm for point-of-care applications. Although a smartphone camera can be utilized to measure the color information of colorimetric sensors, ambient light changes and unknown built-in automatic image correction operations make it difficult to obtain stable color information. This paper utilizes a 3D printed mini light box and performs a calibration procedure with a paper-printed comparison chart and a reference image which overcomes the drawbacks of smartphone cameras and the difficulty in preparing for the calibration procedure. The color adaptation is performed in the CIE 1976 u'v' color space by using the reference paper in order to stabilize the color variations. Non-rigid u'v' curve interpolation is used to produce the high-resolution pH estimate. The final pH value is estimated by using the best-matching method to handle the nonlinear curve properties of multiple color patches. The experimental results obtained using a pH indicator paper show that the proposed algorithm provides reasonably good estimation of pH detection. With paper-printed accurate color comparison charts and smart color adaptation techniques, superior estimation is achieved in the smartphone-based colorimetric pH detection system for point-of-care application.


Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2.
The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of the much more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected the mechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and, moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.


Near-infrared Spectroscopy to Assess Cerebral Perfusion during Head-up Tilt-table Test in Patients with Syncope.
Neurocardiogenic syncope (NCS) is the most common cause of syncope in children and adolescents. Neurocardiogenic syncope occurs secondary to cerebral hypotension because of bradycardia, hypotension, or both. Head-up tilt-table test (HUTT) is the primary diagnostic test. Near-infrared spectroscopy (NIRS) is a noninvasive technology that directly monitors trends in regional tissue oxygen saturations over a specific body region. Placing an NIRS probe over the temporal region allows an indirect measurement of cerebral perfusion. Our hypothesis is that regional tissue oxygen saturation will decrease during an NCS episode and will remain stable in patients without syncope. The investigators conducted a retrospective review of all HUTT utilizing cephalic NIRS performed at our institution from August 2012 to January 2013. Tests were classified as positive, negative, or psychogenic reactions. Paired t-test was used to determine statistical significance of NIRS changes and one-way analysis of variance was used to analyze baseline characteristics among the three groups. Twelve patients were included in the study (female = 10). The average age was 14.4 years (range: 12-17). Five tests were positive for NCS, four were negative, and three demonstrated psychogenic reactions. Patients with a positive test had a sudden, significant decrease in regional tissue oxygen saturations (P = .009) by an average of 11.3 ± 5.2% compared with baseline. The decrease in regional tissue oxygen saturation preceded symptoms, hypotension, and bradycardia in all patients. Regional tissue oxygen saturation levels remained stable in patients with a negative test or psychogenic syncope. NIRS monitoring during HUTT produces a reliable, positive result that precedes clinical signs and symptoms. Further, it helps distinguish NCS from psychogenic syncope.


The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic.
(±)Modafinil ((±)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (±)MOD analogs, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters, and enzymes. Although at a concentration of 10 μM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like, and sigma1 receptors. R-MOD was more selective, but had much lower affinity at the DAT (Ki=3 μM) than JJC8-016 (Ki=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.


13,14-seco-Withanolides from Physalis minima with Potential Anti-inflammatory Activity.
Four new 13,14-seco-withanolides, minisecolides A - D (1 - 4), together with three known analogues 5 - 7, were isolated from the whole plants of Physalis minima. The structures of new compounds were determined on the basis of spectroscopic analysis, including (1) H-, (13) C-NMR, 2D-NMR (HMBC, HSQC, ROESY), and HR-ESI-MS. Evaluation of all isolates for their inhibitory effects on nitric oxide (NO) production was conducted on lipopolysaccaride-activated RAW264.7 macrophages. Compounds 2, 3, 5, and 6 showed inhibitory activities, especially for compound 5 with IC50 value of 3.87 μm.


Per- and polyfluoroalkyl substances, gestational weight gain, postpartum weight retention and body composition in the UPSIDE cohort.
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals found in drinking water and consumer products, resulting in ubiquitous human exposure. PFAS have been linked to endocrine disruption and altered weight gain across the lifespan. A limited and inconsistent body of research suggests PFAS may impact gestational weight gain (GWG) and postpartum body mass index (BMI), which are important predictors of overall infant and maternal health, respectively. In the Understanding Pregnancy Signals and Infant Development (UPSIDE/UPSIDE-MOMs) study (n = 243; Rochester, NY), we examined second trimester serum PFAS (PFOS: perfluorooctanesulfonic acid, PFOA: perfluorooctanoic acid, PFNA: perfluorononanoic acid, PFHxS: perfluorohexanesulfonic acid, PFDA: perfluorodecanoic acid) in relation to GWG (kg, and weekly rate of gain) and in the postpartum, weight retention (PPWR (kg) and total body fat percentage (measured by bioelectrical impedance)). We fit multivariable linear regression models examining these outcomes in relation to log-transformed PFAS in the whole cohort as well as stratified by maternal pre-pregnancy BMI (< 25 vs. = > 25 kg/m2), adjusting for demographics and lifestyle factors. We used weighted quantile sum regression to find the combined influence of the 5 PFAS on GWG, PPWR, and body fat percentage. PFOA and PFHxS were inversely associated with total GWG (PFOA: ß = -1.54 kg, 95%CI: -2.79, -0.30; rate ß = -0.05 kg/week, 95%CI: -0.09, -0.01; PFHxS: ß = -1.59 kg, 95%CI: -3.39, 0.21; rate ß = -0.05 kg/week, 95%CI: -0.11, 0.01) and PPWR at 6 and 12 months (PFOA 6 months: ß = -2.39 kg, 95%CI: -4.17, -0.61; 12 months: ß = -4.02 kg, 95%CI: -6.58, -1.46; PFHxS 6 months: ß = -2.94 kg, 95%CI: -5.52, -0.35; 12 months: ß = -5.13 kg, 95%CI: -8.34, -1.93). PFOA was additionally associated with lower body fat percentage at 6 and 12 months (ß = -1.75, 95%CI: -3.17, -0.32; ß = -1.64, 95%CI: -3.43, 0.16, respectively) with stronger associations observed in participants with higher pre-pregnancy BMI. The PFAS mixture was inversely associated with weight retention at 12 months (ß = -2.030, 95%CI: -3.486, -0.573) amongst all participants. PFAS, in particular PFOA and PFHxS, in pregnancy are associated with altered patterns of GWG and postpartum adiposity with potential implications for fetal development and long-term maternal cardiometabolic health.


Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension.
Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.


Activation of group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol-seeking and modulates c-fos expression in the hippocampus and amygdala.
Major precipitating factors for relapse to drug use are stress and exposure to drug-related environmental stimuli. Group II (mGlu(2/3)) metabotropic glutamate receptors (mGluRs) are densely expressed within circuitries mediating the motivating effects of stress and drug cues and, therefore, may participate in regulating drug-seeking linked to both of these risk factors. Thus, we tested the hypothesis that pharmacological activation of group II mGluRs modifies both stress- and cue-induced ethanol-seeking, using reinstatement models of relapse. In parallel, brain c-fos expression was examined to identify neural substrates for the behavioral effects of group II mGluR activation. The selective mGlu(2/3) agonist LY379268 (1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) (0.3, 1.0, and 3.0 mg/kg, s.c.) dose dependently blocked the recovery of extinguished ethanol-seeking induced by either footshock stress or ethanol-associated discriminative stimuli. These effects were accompanied by modulation of c-fos expression in the hippocampus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and medial parvocellular paraventricular nucleus of the hypothalamus. The results implicate group II mGluRs as a shared neuropharmacological substrate for ethanol-seeking elicited by both drug cues and stress and identify group II mGluRs as promising treatment targets for relapse prevention.


Drp1-Mediated Mitochondrial Metabolic Dysfunction Inhibits the Tumor Growth of Pituitary Adenomas.
Metabolic changes have been suggested to be a hallmark of tumors and are closely associated with tumorigenesis. In a previous study, we demonstrated the role of lactate dehydrogenase in regulating abnormal glucose metabolism in pituitary adenomas (PA). As the key organelle of oxidative phosphorylation (OXPHOS), mitochondria play a vital role in the energy supply for tumor cells. However, few attempts have been made to elucidate mitochondrial metabolic homeostasis in PA. Dynamin-related protein 1 (Drp1) is a member of the dynamin superfamily of GTPases, which mediates mitochondrial fission. This study is aimed at investigating whether Drp1 affects the progression of PA through abnormal mitochondrial metabolism. We analyzed the expression of dynamin-related protein 1 (Drp1) in 20 surgical PA samples. The effects of Drp1 on PA growth were assessed in vitro and in xenograft models. We found an upregulation of Drp1 in PA samples with a low proliferation index. Knockdown or inhibition of Drp1 enhanced the proliferation of PA cell lines in vitro, while overexpression of Drp1 could reversed such effects. Mechanistically, overexpressed Drp1 damaged mitochondria by overproduction of reactive oxygen species (ROS), which induced mitochondrial OXPHOS inhibition and decline of ATP production. The energy deficiency inhibited proliferation of PA cells. In addition, overexpressed Drp1 promoted cytochrome c release from damaged mitochondria into the cytoplasm and then activated the downstream caspase apoptotic cascade reaction, which induced apoptosis of PA cells. Moreover, the decreased ATP production induced by Drp1 overexpressing activated the AMPK cellular energy stress sensor and enhanced autophagy through the AMPK-ULK1 pathway, which might play a protective role in PA growth. Furthermore, overexpression of Drp1 repressed PA growth in vivo. Our data indicates that Drp1-mediated mitochondrial metabolic dysfunction inhibits PA growth by affecting cell proliferation, apoptosis, and autophagy. Selectively targeting mitochondrial metabolic homeostasis stands out as a promising antineoplastic strategy for PA therapy.


Effects of marine reserves versus nursery habitat availability on structure of reef fish communities.
No-take marine fishery reserves sustain commercial stocks by acting as buffers against overexploitation and enhancing fishery catches in adjacent areas through spillover. Likewise, nursery habitats such as mangroves enhance populations of some species in adjacent habitats. However, there is lack of understanding of the magnitude of stock enhancement and the effects on community structure when both protection from fishing and access to nurseries concurrently act as drivers of fish population dynamics. In this study we test the separate as well as interactive effects of marine reserves and nursery habitat proximity on structure and abundance of coral reef fish communities. Reserves had no effect on fish community composition, while proximity to nursery habitat only had a significant effect on community structure of species that use mangroves or seagrass beds as nurseries. In terms of reef fish biomass, proximity to nursery habitat by far outweighed (biomass 249% higher than that in areas with no nursery access) the effects of protection from fishing in reserves (biomass 21% lower than non-reserve areas) for small nursery fish (≤ 25 cm total length). For large-bodied individuals of nursery species (>25 cm total length), an additive effect was present for these two factors, although fish benefited more from fishing protection (203% higher biomass) than from proximity to nurseries (139% higher). The magnitude of elevated biomass for small fish on coral reefs due to proximity to nurseries was such that nursery habitats seem able to overrule the usually positive effects on fish biomass by reef reserves. As a result, conservation of nursery habitats gains importance and more consideration should be given to the ecological processes that occur along nursery-reef boundaries that connect neighboring ecosystems.


Developing and evaluating a mobile driver fatigue detection network based on electroencephalograph signals.
The rapid development of driver fatigue detection technology indicates important significance of traffic safety. The authors' main goals of this Letter are principally three: (i) A middleware architecture, defined as process unit (PU), which can communicate with personal electroencephalography (EEG) node (PEN) and cloud server (CS). The PU receives EEG signals from PEN, recognises the fatigue state of the driver, and transfer this information to CS. The CS sends notification messages to the surrounding vehicles. (ii) An android application for fatigue detection is built. The application can be used for the driver to detect the state of his/her fatigue based on EEG signals, and warn neighbourhood vehicles. (iii) The detection algorithm for driver fatigue is applied based on fuzzy entropy. The idea of 10-fold cross-validation and support vector machine are used for classified calculation. Experimental results show that the average accurate rate of detecting driver fatigue is about 95%, which implying that the algorithm is validity in detecting state of driver fatigue.


A study of pharmacists' involvement in drug use by the elderly.
Three hundred elderly persons in a single Mississippi county were interviewed to determine drug use patterns and relationships with pharmacists. Although three-fourths had used the same pharmacy for longer than five years, only one in six used that pharmacy as their usual source for over-the-counter (OTC) drugs. More than eight percent incorrectly identified the use of their prescription drugs and 140 instances of potential drug interaction were identified. Communications with pharmacists were limited, as only one-fifth had talked with the pharmacist at the time their last prescription was filled and only one in six mentioned the pharmacist as someone they would ask about prescription drugs.


Repurposing of FDA-approved drugs to target MurB and MurE enzymes in Mycobacterium tuberculosis.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is one amongst the top 10 causes of death worldwide. The growing rise in antibiotic resistance compounded with slow and expensive drug discovery has further aggravated the situation. 'Drug repurposing' is a promising approach where known drugs are examined for a new indication. In the present study, we have attempted to identify drugs that could target MurB and MurE enzymes involved in the muramic acid synthesis pathway (Mur Pathway) in Mtb. FDA-approved drugs from two repositories i.e. Drug Bank (1932 drugs) and e-LEA3D (1852 drugs) were screened against these proteins. Several criteria were applied to study the protein-drug interactions and the consensus drugs were further studied by molecular dynamics (MD) simulation. Our study found Sulfadoxine (-7.3 kcal/mol) and Pyrimethamine (-7.8 kcal/mol) to show stable interaction with MurB while Lifitegrast (-10.5 kcal/mol) and Sildenafil (-9.1 kcal/mol) showed most reliable interaction with MurE. Furthermore, binding free energy (ΔGbind), RMSD and RMSF data and the number of hydrogen bonds corroborated the stability of interactions and hence these drugs for repurposing should be explored further.Communicated by Ramaswamy H. Sarma.


ESR detection at 77 K of the hydroxyl radical in the hydration layer of gamma-irradiated DNA.
Previous ESR reports of gamma-irradiated DNA at low temperatures have suggested that hydroxyl radicals are not formed in the first hydration layer of DNA. In this report we show that hydroxyl radicals are produced in low yield. Due to the glassy nature of this hydration layer at low temperature, the hydroxyl radical gives a broad ESR resonance which is not easily detected. Low-field ESR spectra of hydroxyl radicals in an irradiated 6 M CsF aqueous glass are shown to be nearly identical to those found in DNA; however, the yields in the aqueous glass (G = 0.087 to 0.13 mumol/J) are found to be greater than those in DNA's first hydration layer (G = 0.035 +/- 0.02 mumol/J). A large kappa value for destruction of the OH in DNA's hydration layer limits the yield of OH at high doses. The yield of H2O2 (which likely results from hydroxyl radical recombinations that occur both during irradiation and upon annealing) is found to 0.0035 mumol/J in the dose range 65 kGy to 195 kGy. The amount of H2O2 formed corresponds to most of that expected from recombination of the OH trapped at 77 K at the equivalent dose. The low yield of trapped OH radicals in the first hydration layer has implications for possible hole transfer to DNA.


Experimental rheoencephalographic and electroencephalographic investigations on piracetam.
The influence of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the cerebral circulation and brain bioelectrical activity of cortex and mesencephalic reticular formation (RF) was studied in acute experiments on cats which were encéphale isolé preparations. The methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) were used. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and duration of the wave. The arterial blood pressure was followed continuously. The results show that upon piracetam administration (150 mg/kg i.v.) an improvement of the REG parameters of the cortex and RF is observed-an increase of the amplitude and decrease of the values of the anacrotic section of the curve and its relative part. The changes observed indicate a cerebro-vascular resistance decrease and give indirect evidence of cerebral blood volume increase. EEG data are characterized mainly by an increase of alpha-waves, both of cortex and RF. Suggestions for possible mechanism of action of piracetam are made.


Etiological analysis of the sequelae of radiotherapy for nasopharyngeal carcinoma: a follow-up study of 112 cases.
To explore the etiology of the sequelae of radiotherapy for nasopharyngeal carcinoma (NPC) so as to find the possible means for reducing or preventing its occurrence. A total of 112 pathologically confirmed patients with nasopharyngeal carcinoma, who had survived for 5 years following the radiotherapy, were included in this study. Sixty-four patients with the primary carcinoma in the nasopharyngeal region received radiotherapy with the radiation field covering the bilateral anterior ear regions, and in the other 48 patients, adjuvent exposure of the anterior nasal region was administered. The metastases in the cervical lymph nodes were exposed to tangential radiation by 40 Gy X-ray followed by approximately 20 Gy vertical electron beam exposure. Limited mouth-opening and dry mouth occurred mostly during the first 2 years after radiotherapy, and hearing loss in the first year. Neck fibrosis tended to increase with the time elapse after the therapy, and posterior cranial nerve damages showed no signs of time-related occurrence. It was found that the occurrence of neck fibrosis, dry mouth and the nerve injuries did not obviously correlate with the dosage of X-ray exposure in the anterior ear regions, while limited mouth-opening and the hearing loss increased with the radiation dosage. The sequelae did not arise from different radiation field selection as adopted in this study. The radiation dose should be controlled at around 70 Gy for NPC treatment, and for carcinoma remnant in the nasopharyngeal region, additional dose in the cavity would be appropriate. When the X-ray dose of 65 Gy in the neck region fails to result in satisfactory recession of lymph node metastasis, comprehensive treatment involving multiple modalities should be considered.


A Herbivore Tag-and-Trace System Reveals Contact- and Density-Dependent Repellence of a Root Toxin.
Foraging behavior of root feeding organisms strongly affects plant-environment-interactions and ecosystem processes. However, the impact of plant chemistry on root herbivore movement in the soil is poorly understood. Here, we apply a simple technique to trace the movement of soil-dwelling insects in their habitats without disturbing or restricting their interactions with host plants. We tagged the root feeding larvae of Melolontha melolontha with a copper ring and repeatedly located their position in relation to their preferred host plant, Taraxacum officinale, using a commercial metal detector. This method was validated and used to study the influence of the sesquiterpene lactone taraxinic acid β-D-glucopyranosyl ester (TA-G) on the foraging of M. melolontha. TA-G is stored in the latex of T. officinale and protects the roots from herbivory. Using behavioral arenas with TA-G deficient and control plants, we tested the impact of physical root access and plant distance on the effect of TA-G on M. melolontha. The larvae preferred TA-G deficient plants to control plants, but only when physical root contact was possible and the plants were separated by 5 cm. Melolontha melolontha showed no preference for TA-G deficient plants when the plants were grown 15 cm apart, which may indicate a trade-off between the cost of movement and the benefit of consuming less toxic food. We demonstrate that M. melolontha integrates host plant quality and distance into its foraging patterns and suggest that plant chemistry affects root herbivore behavior in a plant-density dependent manner.


Mid-term outcomes of the Helex septal occluder for percutaneous closure of secundum atrial septal defects.
The HELEX Septal Occluder (HSO) was approved by the Food and Drug Administration for closure of secundum atrial septal defects (ASD) in 2006. However, little mid-term follow-up information is available. The object of this study was to examine mid-term outcomes after HSO implantation A retrospective chart review was performed on the first 74 patients who underwent ASD closure with the HSO between 4/00-10/04. Only patients who left the catheterization laboratory after successful implantation and had a minimum follow-up of 5 years were selected for analysis. Thirty-three patients met entry criteria. At implantation the mean age was 10.9 years and the median ASD size was 15.1 mm. At a median follow-up of 88 months, 26 patients had complete ASD closure, 6 had trivial left-right shunts, and 1 had a significant residual shunt having a reintervention. Fluoroscopy, performed in 27 patients revealed a frame fracture in 3 patients (9%), all of whom were asymptomatic and had effective ASD closure. All 3 devices were 30 mm or 35 mm HSO and were left in place. One patient developed first-degree heart block and remained asymptomatic with no progression. There were no instances of late device embolization, cardiac perforation, erosion, or death. Following successful implantation, HSO results in effective closure of secundum ASD in mid-term follow-up. Late complications appear to be rare with the exception of frame fracture, which in this series did not result in clinical sequelae.


Cu-Chelated polydopamine nanoparticles as a photothermal medium and "immunogenic cell death" inducer for combined tumor therapy.
Chemodynamic therapy (CDT) and photothermal therapy (PTT) have been powerful technologies for tumor ablation. However, how to realize efficient CDT and PTT synergetic tumor ablation through a safe and intelligent system, remains a topic of great research value. Herein, a novel Cu-chelated polydopamine nano-system (Cu-PDA) with surface PEGylation and folate (FA) targeting modification (Cu-PDA-FA) was presented as a photothermal agent (PTA), Fenton-like reaction initiator and "immunogenic cell death" inducer to mediate PTT/CDT synergistical tumor therapy and antitumor immune activation. Primarily, the prepared Cu-PDA NPs possessed elevated photothermal conversion efficiency (46.84%) under the near-infrared (NIR) irradiation, bringing about hyperthermic death of tumor cells. Secondly, Cu-PDA catalyzed the generation of toxic hydroxyl radicals (˙OH) in response to the specific tumor microenvironment (TME) with the depletion of GSH, killing tumor cells with high specificity. Interestingly, the increase in local tumor temperature caused by PTT availed the production of ˙OH, and then the produced toxic ˙OH further led the tumor cells to be more sensitive to heat via impeding the expression of heat shock protein, so the synergistically enhanced PTT/CDT in tumor therapy could be achieved. Most importantly, the synergistical PTT/CDT could cause tumor cell death in an immunogenic way to generate in situ tumor vaccine-like functions, which were able to trigger a systemic antitumor immune response, preventing recurrence and metastasis without any other adjuvant supplementation. Overall, these Cu-PDA NPs will provide inspiration for the construction of a versatile nanoplatform for tumor therapy.


Role of Memory T Cells in Allograft Rejection and Tolerance.
Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. Unlike their naïve counterparts, memory T cells reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions. Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells. In the absence of any prior exposure to allogeneic MHC molecules, endogenous alloreactive memory T cells are regularly generated through microbial infections (heterologous immunity). Regardless of their origin, alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action. In addition, we discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings.


Substance Use, Violence, and Antiretroviral Adherence: A Latent Class Analysis of Women Living with HIV in Canada.
We used latent class analysis to identify substance use patterns for 1363 women living with HIV in Canada and assessed associations with socio-economic marginalization, violence, and sub-optimal adherence to combination antiretroviral therapy (cART). A six-class model was identified consisting of: abstainers (26.3%), Tobacco Users (8.81%), Alcohol Users (31.9%), 'Socially Acceptable' Poly-substance Users (13.9%), Illicit Poly-substance Users (9.81%) and Illicit Poly-substance Users of All Types (9.27%). Multinomial logistic regression showed that women experiencing recent violence had significantly higher odds of membership in all substance use latent classes, relative to Abstainers, while those reporting sub-optimal cART adherence had higher odds of being members of the poly-substance use classes only. Factors significantly associated with Illicit Poly-substance Users of All Types were sexual minority status, lower income, and lower resiliency. Findings underline a need for increased social and structural supports for women who use substances to support them in leading safe and healthy lives with HIV.


Immunoregulation of asthma by type 2 cytokine therapies: Treatments for all ages?
Asthma is classically considered to be a disease of type 2 immune dysfunction, since many patients exhibit the consequences of excess secretion of cytokines such as IL-4, IL-5, and IL-13 concomitant with inflammation typified by eosinophils. Mouse and human disease models have determined that many of the canonical pathophysiologic features of asthma may be caused by these disordered type 2 immune pathways. As such considerable efforts have been made to develop specific drugs targeting key cytokines. There are currently available multiple biologic agents that successfully reduce the functions of IL-4, IL-5, and IL-13 in patients, and many improve the course of severe asthma. However, none are curative and do not always minimize the key features of disease, such as airway hyperresponsiveness. Here, we review the current therapeutic landscape targeting type 2 immune cytokines and discuss evidence of efficacy and limitations of their use in adults and children with asthma.


In vivo neuroanatomy of Alzheimer's disease: evidence from structural and functional brain imaging.
In vivo structural (CT, MRI) and functional (SPECT, PET) brain imaging techniques have been widely used to study the neuroanatomy and neurophysiology of Alzheimer's disease (AD) and to identify definite biological markers of the disease. We used meta-analytic methods to synthesize this literature to determine what neuroanatomical structures best differentiate patients with AD from healthy normal controls. A total of 125 studies published between 1984 and 2000 that included 3543 patients with AD and 1698 normal healthy controls met inclusion criteria. We found that measures of the temporal cortices, including the amygdala, hippocampus, and inferior temporal lobes, along with the anterior cingulate cortex, associated with the largest magnitudes of effects and, hence, could serve as the most useful structures to help clinicians differentiate AD from healthy normal aging.


Structure of the Langmuir monolayers with fluorinated ethyl amide and ethyl ester polar heads creating dipole potentials of opposite sign.
This study experimentally checks our previous hypothesis (Petrov, J. G.; Polymeropoulos, E. E.; Moehwald, H. Langmuir 2007, 23, 2623) that different conformations of the fluorinated heads of RCONHCH(2)CF(3) and RCOOCH(2)CF(3) monolayers cause the opposite signs and the striking difference of 1.480 V between their surface potentials Delta V. In situ X-ray diffraction at grazing incidence (GIXD) shows that both monolayers form orthorhombic lattices with closely packed chains tilted to the next-nearest neighbors in the RCONHCH(2)CF(3) film and upright in the RCOOCH(2)CF(3) monolayer. The packing of the chains in the plane perpendicular to them, which excludes the effect of the tilt, shows the same distance between the next-nearest neighbors, but significantly closer nearest neighbors in the RCONHCH(2)CF(3) film. This difference implies a specific anisotropic attraction between the adjacent amide heads. IR reflection absorption spectroscopy (IRRAS) shows that the -CONHCH(2)CF(3) heads have trans conformation and participate in H-bonds forming a -NH...O=C- lateral network. We speculate that such structure hinders the energetically optimal orientation of the hydrophobic -CH(2)CF(3) terminals toward air, so that the (delta+)C-(F (delta-))(3) dipoles at the monolayer/water boundary yield a strong positive contribution to Delta V. In contrast, most of the unbounded by H-bonds -COOCH(2)CF(3) heads statistically orient their hydrophobic (delta+)C-(F (delta-))(3) dipoles toward air, yielding a negative average dipole moment at the monolayer/water boundary and negative surface dipole potential.


[Combined prophylaxis of recurrent lower urinary tract infections in children and pregnant women].
The use of the combined herbal preparation Cystenium II for the prevention of recurrent lower urinary tract infections, including those in children and pregnant women, is described in the review. The etiological component of infectious and inflammatory diseases of the lower urinary tract and specific features of the interaction of microorganisms with bladder mucosa were studied. A detailed analysis of pharmacodynamic effects of Cysteniums II components is provided. The specific features of the treatment of acute cystitis in pregnant women and children older than 7 years are presented.