Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.
A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.


Oxidative stress status increase in patients with nonischemic heart failure.
It was the aim of this study to investigate the serum oxidative stress level in nonischemic patients with heart failure (HF). The study included 37 patients who presented to the Department of Cardiology, Suleyman Demirel University, Isparta, Turkey, with a diagnosis of asymptomatic HF (New York Heart Association class I-II). The patients had a left ventricular (LV) ejection fraction (EF) of ≤40% and normal coronary arteries or nonsignificant stenosis (stenosis <40%). In addition, 30 age- and sex-matched normal patients were selected as the control group. Clinical and laboratory characteristics presumed to be associated with oxidative stress were evaluated. Demographic characteristics were comparable. However, creatinine and potassium levels were higher in the HF than in the control group. Total oxidative status [2.42 μmol H2O2 Eq/l (range 0.74-5.86) vs. 1.81 μmol H2O2 Eq/l (range 0.42-3.45); p < 0.01], oxidative stress index [2.24 (range 0.63-5.33) vs. 1.53 (range 0.28-2.51); p < 0.01] and uric acid (6.1 ± 1.8 vs. 4.4 ± 1.1 mg/dl; p < 0.01) levels were significantly higher in the HF than in the control group. The total antioxidant capacity was similar in both groups [1.22 mmol Trolox Eq/l (range 0.61-1.99) vs. 1.18 mmol Trolox Eq/l (range 0.82-1.80); p = 0.77]. The γ-glutamyltransferase levels were also comparable in both groups [32 U/l (range 11-106) vs. 23 U/l (range 11-72); p = 0.10]. The oxidative stress levels were higher in HF patients, and hence, oxidative stress may play an important role in poor prognosis of HF. Therefore, antioxidant treatment might be reasonable.


STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome.
To determine the long-term effects of in utero progesterone exposure in twin children. This study evaluated the health and developmental outcomes of all surviving children born to mothers who participated in a double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth in twin pregnancies (STOPPIT, ISRCTN35782581). Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory and the Health Utilities Index. Record linkage was successfully performed on at least one record in 759/781 (97%) children eligible for follow-up. There were no differences between progesterone-exposed and placebo-exposed twins with respect to incidence of death, congenital anomalies and hospitalisation, nor on routine national child health assessments. Questionnaire responses were received for 324/738 (44%) children. The mean age at questionnaire follow-up was 55.5 months. Delay in at least one developmental domain on the Child Development Inventory was observed in 107/324 (33%) children, with no evidence of difference between progesterone-exposed and placebo-exposed twins. There was no evidence of difference between the progesterone and placebo groups in global health status assessed using the Health Utilities Index: 89% of children were rated as having 'excellent' health and a further 8% as having 'very good' health. In this cohort of twin children there was no evidence of a detrimental or beneficial impact on health and developmental outcomes at three to six years of age due to in utero exposure to progesterone.


Review of psychosocial stress and asthma: an integrated biopsychosocial approach.
Environmental stressors may impact asthma morbidity through neuroimmunological mechanisms which are adversely impacted and/or buffered y social networks, social support, and psychological functioning. In addition, life stress may impact on health beliefs and behaviours that may affect asthma management. Whereas earlier psychosomatic models have supported a role for psychological stress in contributing to variable asthma morbidity among those with existing disease, a growing appreciation of the interactions between behavioural, neural, endocrine, and immune processes suggest a role for these psychosocial factors in the genesis of asthma as well. While a causal link between stress and asthma has not bee established, this review provides a framework in which we can begin to see links between these systems that might provide new insights to guide future explorations. The complexity of these interactions underscore the need for a multidisciplinary approach which combines the idea that the origin of asthma is purely psychogenic in nature with the antithetical consideration that the biological aspects are all important. These distinctions are artificial, and future research that synthesizes biological, psychological, sociocultural, and family parameters is urgently needed to further our understanding of the rising burden of asthma.


Finding future high-cost cases: comparing prior cost versus diagnosis-based methods.
To examine the value of two kinds of patient-level dat a (cost and diagnoses) for identifying a very small subgroup of a general population with high future costs that may be mitigated with medical management. The study used the MEDSTAT Market Scan (R) Research Database, consisting of inpatient and ambulatory health care encounter records for individuals covered by employee- sponsored benefit plans during 1997 and 1998. Prior cost and a diagnostic cost group (DCG) risk model were each used with 1997 data to identify 0.5-percent-sized "top groups" of people most likely to be expensive in 1998. We compared the distributions of people, cost, and diseases commonly targeted for disease management for people in the two top groups and, as a bench mark, in the full population. the prior cost- and DCG-identified top groups overlapped by only 38 percent. Each top group consisted of people with high year-two costs and high rates of diabetes, heart failure, major lung disease, and depression. The DCG top group identified people who are both somewhat more expensive ($27,292 vs. $25,981) and more likely ( 49.4 percent vs. 43.8 percent ) th an the prior-cost top group to have at least one of the diseases commonly targeted for disease management. The overlap group average cost was $46,219. Diagnosis-based risk models are at least as powerful as prior cost for identifying people who will be expensive. Combined cost and diagnostic data are even more powerful and more operation ally useful, especially because the diagnostic information identifies the medical problems that may be managed to achieve better out comes and lower costs.


Survey on antibiotic sensitivity of Neisseria gonorrhoeae strains isolated in China, 1987-1992.
The appearance and the endemic of penicillinase-producing Neisseria gonorrhoeae (PPNG) and other resistant strains cause much difficulty in the treatment of gonorrhea. To keep surveillance of the strains is important for the control of gonorrhea nationwide. To know the resistance to antibiotics of Neisseria gonorrhoeae strains isolated in China. The minimum inhibitory concentration (MIC) to penicillin, spectinomycin, and cephalosporins was determined by the agar plate dilution test in strains of N. gonorrhoeae submitted from six cities in various areas of the country during the period 1987-1992, and the prevalence of penicillinase-producing N. gonorrhoeae strains were examined by the rapid idometric method. The resistant strains to penicillin (MIC > or = 1.0 microgram/ml) accounted for 57.5% of all isolates. The resistant strains to spectinomycin (MIC > or = 128 micrograms/ml) made up 1.3% and the strains which had a MIC closing resistance (MIC = 64 micrograms/ml) accounted for 4%. There were 18 PPNG strains (4.3%) in 419 isolates from Nanjing and Nanning city. The resistant strains to ceftrixone and cefotaxime accounted for 2.6% and 4.2%, respectively. The situation of N. gonorrhoeae resistance to penicillin is rather serious in the country and relevant measures should be taken in the choice of therapeutic drugs, the follow-up of patients and the surveillance of gonorrhea.


An effort to improve electronic health record medication list accuracy between visits: patients' and physicians' response.
To evaluate the efficacy of a secure web-based patient portal called Patient Gateway (PG) in producing more accurate medication lists in the electronic health record (EHR), and whether sending primary care physicians (PCPs) a clinical message updating them on the information their patients provided caused physicians to update the EHR medication list. We compared the medication list accuracy of 84 patients using PG with that of 79 who were not. Patient-reported medication discrepancies were noted in the EHR in a clinical note by research staff and a message was sent to the participants' PCPs notifying them of the updated information. Participants were taking 665 medications according to the EHR, and reported 273 additional medications. A lower percentage of PG users' drug regimens (54% versus 61%, p=0.07) were reported to be correct than those of PG non-users, although PG users took significantly more medications than their non-user counterparts (5.0 versus 3.1 medications, p=0.0001). Providing patient-reported information in a clinical note and sending a clinical message to the primary care doctor did not result in PCPs updating their patients' EHR medication lists. Medication lists in EHRs were frequently inaccurate and most frequently overlooked over-the-counter (OTC) and non-prescription drugs. Patients using a secure portal had just as many discrepancies between medication lists and self-report as those who did not, and notifying physicians of discrepancies via e-mail had no effect.


Do anxiety and depression statuses differ in differentpolycystic ovary syndrome phenotypes?
To evaluate psychological parameters and health quality profiles in women with reproductive polycystic ovary syndrome (PCOS) phenotypes and age matched controls. The study groups included 101 women with PCOS (54 with the National Institutes of Health [NIH] phenotype and 47 with the non-NIH phenotype) and 49 healthy female controls. The participants completed anxiety and depression scales and four quality of life domains. We identified the women with PCOS as having a 3.39 times increased risk for depression (subscale ≥ 7) and a 3.64 times increased risk for anxiety (subscale ≥ 10) compared to the controls. Both NIH and non-NIH phenotypes showed similar rates of depression (46.3% vs. 46.8%, respectively; P = 0.57) and anxiety (31.5% vs. 36.2%, respectively; P = 0.47). Regarding the quality of life scale, the women with NIH PCOS had significantly lower mental health scores compared to those with non-NIH PCOS (P = 0.03). Furthermore, while mental health scores were similar in the women with PCOS and the controls, physical health scores were significantly lower in the women with PCOS (P = 0.007). Nearly half of the women with PCOS had higher depression scores and one third had higher anxiety scores. Thus, psychiatric evaluations appear necessary for PCOS patients in order to diagnose and treat clinical depression and anxiety.


Determinants of parasitoid communities of willow-galling sawflies: habitat overrides physiology, host plant and space.
Studies on the determinants of plant-herbivore and herbivore-parasitoid associations provide important insights into the origin and maintenance of global and local species richness. If parasitoids are specialists on herbivore niches rather than on herbivore taxa, then alternating escape of herbivores into novel niches and delayed resource tracking by parasitoids could fuel diversification at both trophic levels. We used DNA barcoding to identify parasitoids that attack larvae of seven Pontania sawfly species that induce leaf galls on eight willow species growing in subarctic and arctic-alpine habitats in three geographic locations in northern Fennoscandia, and then applied distance- and model-based multivariate analyses and phylogenetic regression methods to evaluate the hierarchical importance of location, phylogeny and different galler niche dimensions on parasitoid host use. We found statistically significant variation in parasitoid communities across geographic locations and willow host species, but the differences were mainly quantitative due to extensive sharing of enemies among gallers within habitat types. By contrast, the divide between habitats defined two qualitatively different network compartments, because many common parasitoids exhibited strong habitat preference. Galler and parasitoid phylogenies did not explain associations, because distantly related arctic-alpine gallers were attacked by a species-poor enemy community dominated by two parasitoid species that most likely have independently tracked the gallers' evolutionary shifts into the novel habitat. Our results indicate that barcode- and phylogeny-based analyses of food webs that span forested vs. tundra or grassland environments could improve our understanding of vertical diversification effects in complex plant-herbivore-parasitoid networks.


Small Airways Disease, Biomarkers and COPD: Where are We?
The response to treatment and progression of Chronic Obstructive Pulmonary Disease (COPD) varies significantly. Small airways disease (SAD) is being increasingly recognized as a key pathological feature of COPD. Studies have brought forward pathological evidence of small airway damage preceding the development of emphysema and the detection of obstruction using traditional spirometry. In recent years, there has been a renewed interest in the early detection of SAD and this has brought along an increased demand for physiological tests able to identify and quantify SAD. Early detection of SAD allows early targeted therapy and this suggests the potential for altering the course of disease. The aim of this article is to review the evidence available on the physiological testing of small airways. The first half will focus on the role of lung function tests such as maximum mid-expiratory flow, impulse oscillometry and lung clearance index in detecting and quantifying SAD. The role of Computed Tomography (CT) as a radiological biomarker will be discussed as well as the potential of recent CT analysis software to differentiate normal aging of the lungs to pathology. The evidence behind SAD biomarkers sourced from blood as well as biomarkers sourced from sputum and broncho-alveolar lavage (BAL) will be reviewed. This paper focuses on CC-16, sRAGE, PAI-1, MMP-9 and MMP-12.


Niacin: an old drug rejuvenated.
Niacin has long been used in the treatment of dyslipidemia and cardiovascular disease. Recent research on niacin has been focused on understanding the mechanism of action of niacin and preparation of safer niacin formulations. New findings indicate that niacin does the following: 1) it inhibits hepatic diacylglycerol acyltransferase 2, resulting in inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; 2) it decreases the surface expression of hepatic adenosine triphosphate synthase beta-chain, leading to decreased holoparticle high-density lipoprotein catabolism and increased high-density lipoprotein levels; and 3) it increases redox potential in arterial endothelial cells, resulting in inhibition of redox-sensitive genes. Flushing, an adverse effect of niacin, results from niacin receptor GPR109A-mediated production of prostaglandin D2 and E2 via DP1 and EP2/4 receptors. DP1 receptor antagonist (laropiprant) attenuates the niacin flush. A reformulated preparation of extended-release niacin (Niaspan; Abbott, Abbott Park, IL) lowers flushing compared with an older Niaspan formulation. These advancements in niacin research have rejuvenated its use for the treatment of dyslipidemia and cardiovascular disease.


Effects of exercise and glucose administration on content of insulin-sensitive glucose transporter in equine skeletal muscle.
To characterize insulin-sensitive glucose-transporter (GLUT-4) protein in equine tissues and determine effects of exercise and glucose administration on content of GLUT-4 protein in equine skeletal muscle. Tissue samples from 9 horses. Western blot analyses were performed on crude membrane preparations of equine tissues to characterize GLUT-4. In a crossover, randomized study, horses were strenuously exercised for 3 consecutive days and then administered 13.5% glucose or isotonic saline (0.9% NaCl; control) solution, i.v., at similar infusion rates for 12.1 hours. Samples were collected from the middle gluteal muscle before and after exercise and 10.1 hours after completion of an infusion and used for measurements of glycogen concentration and total content of GLUT-4 protein. Immunoblot analyses detected specifically immunoreactive bands for GLUT-4 in insulin-sensitive tissues. Content of GLUT-4 protein in skeletal muscle increased significantly by 27.3 and 12.3% 22.2 hours after exercise for control and glucose groups, respectively. Intravenous infusion of glucose resulted in a significantly higher rate of glycogenesis, compared with results for the control group (mean +/- SD, 3.98 +/- 0.61 and 1.47 +/- 0.20 mmol/kg/h, respectively). Despite enhanced glycogenesis, we did not detect an increase in content of GLUT-4 protein after glucose infusion, compared with values after exercise. GLUT-4 protein was expressed in equine skeletal and cardiac muscles. Exercise increased total content of GLUT-4 protein in skeletal muscle, and replenishment of muscle glycogen stores after glucose infusion attenuated the exercise-induced increase in the content of GLUT-4 protein in equine skeletal muscle.


CONCERNING THE INFLUENCE OF POLARIZED LIGHT ON THE GROWTH OF SEEDLINGS.
While these experiments are not exhaustive, a sufficient number have been made to warrant the statement that the effect of polarized light of the visible spectrum on the growth of various seedlings and See PDF for Structure more particularly on the growth of Lupinus albus is somewhat different from that of non-polarized light. This is especially convincing in view of the results obtained with double sets of plants which were alternately exposed to polarized and non-polarized lights of the same intensities and at the same temperature. In every experiment thus performed the set which was placed in a polarizing chamber grew better. It is, furthermore, interesting to note that the phenomenon above observed did not take place when the seed portion of the plants was protected from light by wrapping with tinfoil. This agrees well with previous findings concerning the action of diastase on starch in polarized light. The above researches will be continued on a more elaborate scale but the results so far obtained are deemed worthy of publication in the form of a preliminary communication at the present time.


Susceptibility of genital mycoplasmas to antimicrobial agents.
The susceptibility of 11 T-strains, 12 strains of Mycoplasma hominis, and a single strain of M. fermentans to 15 antimicrobial agents was determined by study of inhibition of metabolic activity in a broth dilution system. All three species were inhibited by tetracycline, chloramphenicol, streptomycin, gentamicin, and kanamycin, and were relatively resistant to cephalothin, cephaloridine, polymyxin, vancomycin, and ampicillin. Three antimicrobial agents had significant differential effects on these species. Erythromycin was more active against T-strains than against M. hominis or M. fermentans. Lincomycin, clindamycin, and nitrofurantoin had greater activity against M. hominis and M. fermentans than against T-strains. The activity of the drugs tested was generally uniform over a wide range of inocula. The effect of pH and the difference between minimal inhibiting and minimal mycoplasmacidal concentrations of the drugs tested were consistent with expectations based on the effects of these drugs on bacteria.


[Diversity of vegetation during its recovery from a catastrophic flood of the Medium Paraná River (Argentina)].
River floodplains have a high biological diversity that is intensely influenced by vegetation dynamics, changes in space and time scales, and the river's hydrological regime. The vegetation composition of the medium and lower Paraná River has been analyzed previously, with different approaches and criteria that cannot be compared. The aim of this study is to analyze the diversity of the herbaceous vegetation over long time spans, from its regeneration after a catastrophic flood to its recovery, in the North and South sites of the flooding valley of the Medium Paraná River. The first sampling of a pioneer community was performed after the 1982-83 catastrophic flood, and included the surveillance of two plots in two successive recovery stages. Floristic composition and cover-abundance of all species were recorded per plot. Floristic richness, using jackknife, Shannon and Hurlbert diversity and Simpson dominance curves were calculated for each site and for each survey, using EcoSim (software). Floristic richness was higher in the North of Medium Paraná, while dominance was higher in the South. Diversity indexes did not varied significantly and resulted in relatively stable values, because its components compensate each other.


[Medline criteria for scientific journals selection. Methodology and indicators. Application to Spanish medical journals paying special attention to public health].
Due to the strict selection process applied to its indexed journals, Medline is the most prestigious database in the Health and medicine field. The aim of this paper is both to analyze its selection criteria and translate into indicators that can be applied to Spanish medical journals willing to enter the Index Medicus. Analysis samples and methodology to apply obtained from the five groups of criteria considered by Medline (namely, Scope and coverage, Quality of contents, Quality of editorial work, Production quality and Audience) are proposed. A list of qualitative and quantitative indicators related to the five groups of criteria used by Medline is presented; namely, journal scientific output in the national and international context of the discipline, citation, analysis of the editorial committees, the editorial process and the peer-review system, indicators on compliance with the Vancouver guidelines, journal layout and informational quality, attractiveness, audience, journal visibility and interest as regards Medline goals.


Diabetes and its care--what do patients expect?
A sample of 77% of the non-insulin dependent diabetics aged 30-70 years from two urban practices offering no structured diabetic care were interviewed. The 55 patients (mean age 60 years) were asked about their experiences and expectations of diabetes and the health professionals involved in their care. Twenty-six patients attended the hospital diabetic clinic regularly but 13 patients received no review at all; 46 patients wanted their general practitioner to be involved in future care and only six wanted to continue with hospital review alone. Patients gave hospital doctors and general practitioners similar high ratings for knowledge of diabetes and its management but general practitioners and practice nurses were rated more highly for communication and accessibility. The aspect of care valued most was being given clear information about diabetic management. Twenty two patients thought that diabetes would have a significant impact on their future health and 35 rated regular diabetic review as extremely important in keeping themselves healthy. Most patients felt it likely that they would have a high blood glucose level most of the time and develop diabetic complications. Little difference was found between the views of clinic attenders and non-attenders, and there was no evidence that non-attenders had actively rejected review. These non-insulin dependent diabetics considered diabetes to be a serious disorder warranting regular care and expressed confidence in the primary care team's ability to provide such care.


Long noncoding RNA NBAT1 inhibits autophagy via suppression of ATG7 in non-small cell lung cancer.
Autophagy is critical for the survival of cancer cells. It has been reported that long noncoding RNA (lncRNA) neuroblastoma associated transcript 1 (NBAT1) exerts as a tumor suppressor in some cancers. However, the role of NBAT1 in autophagy of non-small cell lung cancer (NSCLC) remains unknown. Here, it was reported that NBAT1 overexpression inhibited autophagy, while knockdown of NBAT1 induced autophagy in NSCLC cells. Further mechanistic study showed that NBAT1 interacted with PSMD10 and promoted its degradation, and then inhibited the occupancy of PSMD10 and HSF1 in the ATG7 promoter to suppress ATG7 transcription. A significantly negative correlation between NBAT1 and ATG7 levels was observed in NSCLC tissue. The prognoses of NSCLC patients with low expression of NBAT1 were much worse than those with high-level NBAT1. Moreover, NBAT1 negatively regulated cell viability, clonogenicity, and chemoresistance through inhibition of autophagy. Our findings suggest that the NBAT1-PSMD10-ATG7 axis may be an attractive strategy in NSCLC treatment by suppressing autophagy and chemoresistance.


Educational and organisational interventions used to improve the management of hypertension in primary care: a systematic review.
The optimal way in which to organise and deliver care to patients with hypertension has not been clearly identified. To determine the effectiveness of educational and organisational strategies used to improve control of blood pressure. Systematic review of randomised controlled trials (RCTs). Quantitative pooling of RCT data on patients with hypertension that evaluated the following interventions: (1) self monitoring, (2) educational interventions directed to the patient, (3) educational interventions directed to the health professional, (4) health professional (nurse or pharmacist) led care, (5) organizational interventions that aimed to improve the delivery of care, (6) appointment reminder systems. Fifty-six RCTs met our inclusion criteria. The methodological quality of included studies was variable. An organised system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce blood pressure (weighted mean difference -8.2/-4.2mmHg, -11.7/-6.5mmHg, -10.6/-7.6mmHg for three strata of entry blood pressure) and all-cause mortality at 5 years follow-up (6.4% versus 7.8%, difference 1.4%) in a single large RCT (the Hypertension Detection and Follow-up study). Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in diastolic blood pressure, weighted mean difference (WMD): -2.03 mmHg, 95% confidence interval (CI) = -2.7 to -1.4 mmHg. Educational interventions directed towards physicians were associated with small reductions in systolic blood pressure (WMD) -2.0mmHg, 95% CI = -3.5 to -0.6mmHg and diastolic blood pressure (WMD) -0.4mmHg, 95% CI -1.1 to 0.3mmHg. General practices and community-based clinics need to have an organised system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. These findings have important implications for recommendations concerning implementation of structured delivery of care in hypertension guidelines.


Recommendations for reporting economic evaluations of haemophilia prophylaxis: a nominal groups consensus statement on behalf of the Economics Expert Working Group of The International Prophylaxis Study Group.
The need for clearly reported studies evaluating the cost of prophylaxis and its overall outcomes has been recommended from previous literature. To establish minimal ''core standards'' that can be followed when conducting and reporting economic evaluations of hemophilia prophylaxis. Ten members of the IPSG Economic Analysis Working Group participated in a consensus process using the Nominal Groups Technique (NGT). The following topics relating to the economic analysis of prophylaxis studies were addressed; Whose perspective should be taken? Which is the best methodological approach? Is micro- or macro-costing the best costing strategy? What information must be presented about costs and outcomes in order to facilitate local and international interpretation? The group suggests studies on the economic impact of prophylaxis should be viewed from a societal perspective and be reported using a Cost Utility Analysis (CUA) (with consideration of also reporting Cost Benefit Analysis [CBA]). All costs that exceed $500 should be used to measure the costs of prophylaxis (macro strategy) including items such as clotting factor costs, hospitalizations, surgical procedures, productivity loss and number of days lost from school or work. Generic and disease specific quality of lífe and utility measures should be used to report the outcomes of the study. The IPSG has suggested minimal core standards to be applied to the reporting of economic evaluations of hemophilia prophylaxis. Standardized reporting will facilitate the comparison of studies and will allow for more rational policy decisions and treatment choices.


Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib.
As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. EGFR-targeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment.


Resuscitated sudden cardiac death due to severe hypokalemia caused by teff grain herbal tea: A case report.
Obesity is a common health problem and the prevalence is increasing worldwide. The improper and unregulated use of unconventional therapies, especially herbal treatment methods, has grown due to widespread availability. In our case, a 41-year-old male patient developed palpitation, confusion, loss of consciousness, and cardiac arrest while at home. An emergency medical team was called and chest compressions were performed by his wife until the medical team arrived. Ventricular fibrillation was detected on the monitor 5 minutes after the cardiac arrest occurred and the patient was defibrillated. A physical evaluation revealed hypotension and tachycardia. Electrocardiography (ECG) showed a fast idioventricular rhythm with capture and fusion beats and evident J waves in leads DII, DIII, and aVF. Brain magnetic resonance imaging and thoracic tomography revealed no pathology to explain his clinical condition and the coronary angiography results were not significant. The laboratory parameters included potassium (K): 2.23 mEq/L, ionized K (arterial blood): 2.43 mEq/L, sodium: 142 mEq/L, calcium: 9.3 mg/dL, creatinine: 1.6 mg/dL, pH: 7.29, cardiac troponin I: 0.12 (normal range: 0-0.11 ng/mL) and creatinine kinase mass: 8.3 (normal range: 0-3.23 ng/mL). After fluids and electrolyte replacement therapy were administered, the ECG results revealed narrow QRS complex atrial fibrillation followed by a normal sinus rhythm with a 490 ms corrected QT interval. The patient was extubated in follow-up. There were no risk factors for coronary artery disease, no history of drug or other substance use, and no exposure to excessive emotional or physical stress. The patient said that he had been consuming a large quantity of teff tea for 5 days to lose weight. He was discharged without any complications and has been asymptomatic in 9 months of follow-up. The inappropriate use of weight loss alternatives, especially herbal therapies such as teff tea, and the incidence of associated side effects are increasing due to wide availability and easy access. The general population should be warned about this issue.


Influence of ischemic core muscle fibers on surface depolarization potentials in superfused cardiac tissue preparations: a simulation study.
Thin-walled cardiac tissue samples superfused with oxygenated solutions are widely used in experimental studies. However, due to decreased oxygen supply and insufficient wash out of waste products in the inner layers of such preparations, electrophysiological functions could be compromised. Although the cascade of events triggered by cutting off perfusion is well known, it remains unclear as to which degree electrophysiological function in viable surface layers is affected by pathological processes occurring in adjacent tissue. Using a 3D numerical bidomain model, we aim to quantify the impact of superfusion-induced heterogeneities occurring in the depth of the tissue on impulse propagation in superficial layers. Simulations demonstrated that both the pattern of activation as well as the distribution of extracellular potentials close to the surface remain essentially unchanged. This was true also for the electrophysiological properties of cells in the surface layer, where most relevant depolarization parameters varied by less than 5.5 %. The main observed effect on the surface was related to action potential duration that shortened noticeably by 53 % as hypoxia deteriorated. Despite the known limitations of such experimental methods, we conclude that superfusion is adequate for studying impulse propagation and depolarization whereas repolarization studies should consider the influence of pathological processes taking place at the core of tissue sample.


The Impact of the COVID-19 Pandemic on Rural Food Security in High Income Countries: A Systematic Literature Review.
Prior to the COVID-19 pandemic, rural-dwelling people in high-income countries were known to have greater challenges accessing healthy food than their urban counterparts. The COVID-19 pandemic has impacted food supplies across the world, and public health restrictions have changed the way people shop for food, potentially exacerbating food insecurity. This systematic literature review aimed to synthesize the available evidence on the impact of the COVID-19 pandemic on aspects of food insecurity in rural populations residing in high-income countries. Five electronic databases were searched, identifying 22 articles that assessed food insecurity prevalence or data on food availability, access, utilization and the stability of the food supply in rural populations during the COVID-19 pandemic. Ten studies examined the prevalence of food insecurity in rural populations, with the reported prevalence ranging from 15% to 95%. Where rural/urban comparisons were presented, most studies (n = 5; 71%) reported that food insecurity was significantly higher in rural regions. Five studies examined the availability of food and eight studies examined access to food, identifying that rural populations often had lower food availability and access to food during the pandemic. In contrast, two studies identified positive effects such as more gardening and increased online access to food. Rural populations experienced multiple changes to food utilization, such as reduced diet quality and food safety observed in eight studies, but this was not shown to be different from urban populations. Additionally, the food supply in rural regions was perceived to be affected in two studies. The results of this review may be used to inform region-specific mitigation strategies to decrease the impact of the current COVID-19 pandemic and future global events on food security. However, the lack of consistency in study outcomes in research on rural populations limits the identification of priority areas for intervention at a global-scale.


Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells.
In this study a flow cytometric technique for detecting cytoplasmic perforin (P) has been used to quantify age-related changes in perforin expression in human peripheral blood lymphocytes (PBL). Proportions of P+ lymphocytes increased after birth, but declined rapidly after the age of 70 years. This was true for both T cells and CD16(+) and CD56(+) natural killer (NK) cells. Children showed in addition to high levels of perforin positive CD8(+) cells a much higher proportion of CD4(+)P+ cells than the other age groups. In elderly individuals there was also a highly significant reduction in mean levels of perforin per cell as compared with all other groups (P < .05 to .001). Adult women had consistently higher mean levels of perforin per cell than adult men for all P+ cell phenotypes. Functional tests clearly showed the deficiency in early spontaneous cytotoxic potential of PBL from elderly persons due to relative P deficiency, which can be corrected by stimulation of cytolytic cells with target cells and interleukin-2 (IL-2). The deficiency in cytolytic activity on the contact with target cells may have implications for antiviral and antitumor immunity in elderly persons.


Bovine virus diarrhoea-mucosal disease and border disease in Egypt.
In Egypt, bovine virus diarrhoea-mucosal disease (BVD-MD) was initially detected as the result of a serological survey of cattle and sheep, using the serum neutralisation test. In 1970, the causal pestivirus was isolated from bovine calves and buffalo calves with pneumonia and enteritis. Mixed viral infections were also prevalent. Cases of immune tolerance were identified. The Egyptian industry had complained of unthrifty cattle and high death rates of bovine calves and buffalo calves. A rinderpest outbreak in 1982 involved some cattle and buffalo which had been vaccinated against the disease, and such animals were positive to the gel diffusion test for BVD-MD pestivirus. Extensive immunosuppression due to BVD MD virus was suspected, because the attenuated cell-culture vaccine against rinderpest, issued in Egypt since 1965, had not been tested for freedom from non-cytopathic BVD-MD virus. Experimental infection of susceptible sheep with BVD-MD virus resulted in symptoms of Border disease. Innocuity of the attenuated C24V bovine pestivirus vaccine for animal tissues and the immune system of calves was confirmed.


Nectin4 is a potential therapeutic target for asthma.
Nectins comprise a family of cellular adhesion molecules involved in Ca2+-independent cellular adhesion. Neither the biological significance nor clinical potential of Nectin4 for asthma has been investigated. The aims of this study were to elucidate the role of Nectin4 in airway inflammation and to determine the relationship between Nectin4 and clinical variables in patients with asthma. The relationship between Nectin4 levels in the blood of asthmatic patients and clinical variables was examined. Dermatophagoides pteronyssinus 1 (Der p1)-exposed normal human bronchial epithelial (NHBE) cells, and Nectin4-deficient (Nectin4-/-) and wild-type (WT) mice sensitized/challenged with ovalbumin (OVA), were used to investigate the involvement of Nectin4 in the pathogenesis of bronchial asthma via the Src/Rac1 pathway. Plasma Nectin4 levels were significantly higher in asthmatic patients than controls and correlated with specific IgE D1, D2, lung function. The ROC curves for Nectin4 levels differed between asthma patients and controls. Nectin4/Afadin and Src/Rac1 levels were significantly increased in NHBE cells exposed to Der p1, but decreased in NHBE cells treated with Nectin4 siRNA. Airway obstruction and inflammation, as well as the levels of Th2 cytokines, Nectin4, and Src/Rac1, were increased in WT OVA/OVA mice compared with WT sham mice. Nectin4 knockdown resulted in lower levels of Afadin and Src/Rac1 in Nectin4-/-OVA/OVA than WT OVA/OVA mice. These results suggest that Nectin4 is involved in airway inflammation and may be a therapeutic target in patients with asthma.


Dynamical tunneling in macroscopic systems.
We investigate macroscopic dynamical quantum tunneling (MDQT) in the driven Duffing oscillator, characteristic for Josephson junction physics and nanomechanics. Under resonant conditions between stable coexisting states of such systems we calculate the tunneling rate. In macroscopic systems coupled to a heat bath, MDQT can be masked by driving-induced activation. We compare both processes, identify conditions under which tunneling can be detected with present day experimental means and suggest a protocol for its observation.


Evaluation of renal disturbance in animal models of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by hyperandrogenism and hyperinsulinemia, followed by luteinizing hormone and follicle-stimulating hormone deficiency. PCOS conditions cause metabolic disorders that increase uric acid levels and malondialdehyde (MDA) levels. Animal models of PCOS have been used extensively in research to study the pathogenesis, clinical characteristics, and treatment of PCOS. This study aimed to identify the pathological mechanisms underlying renal dysfunction in PCOS by observing several parameters, including blood urea nitrogen (BUN), creatinine, uric acid, and renal MDA levels. This research was an experimentally designed study using a Wistar rat (Rattus norvegicus) as an animal model of PCOS which were divided into three groups: negative control group (n = 6), Testosterone propionate (TP) induction group (n = 6), and estradiol valerate (EV) induction group (n = 6). According to statistical analysis it indicated that induction of TP and EV can increase blood uric acid levels in PCOS model rats (p < 0.05), TP induction can increase kidney BUN and MDA levels significantly (p < 0.05), However, the observation of creatinine levels did not show significant differences in all treatment groups (p > 0.05). Based on the results of this study, it can be concluded that the induction of animal models with TP can trigger significant renal damage compared to EV.


In silico and in vitro arboviral MHC class I-restricted-epitope signatures reveal immunodominance and poor overlapping patterns.
The present work sought to identify MHC-I-restricted peptide signatures for arbovirus using in silico and in vitro peptide microarray tools. First, an in-silico analysis of immunogenic epitopes restricted to four of the most prevalent human MHC class-I was performed by identification of MHC affinity score. For that, more than 10,000 peptide sequences from 5 Arbovirus and 8 different viral serotypes, namely Zika (ZIKV), Dengue (DENV serotypes 1-4), Chikungunya (CHIKV), Mayaro (MAYV) and Oropouche (OROV) viruses, in addition to YFV were analyzed. Haplotype HLA-A*02.01 was the dominant human MHC for all arboviruses. Over one thousand HLA-A2 immunogenic peptides were employed to build a comprehensive identity matrix. Intending to assess HLAA*02:01 reactivity of peptides in vitro, a peptide microarray was designed and generated using a dimeric protein containing HLA-A*02:01. The comprehensive identity matrix allowed the identification of only three overlapping peptides between two or more flavivirus sequences, suggesting poor overlapping of virus-specific immunogenic peptides amongst arborviruses. Global analysis of the fluorescence intensity for peptide-HLA-A*02:01 binding indicated a dose-dependent effect in the array. Considering all assessed arboviruses, the number of DENV-derived peptides with HLA-A*02:01 reactivity was the highest. Furthermore, a lower number of YFV-17DD overlapping peptides presented reactivity when compared to non-overlapping peptides. In addition, the assessment of HLA-A*02:01-reactive peptides across virus polyproteins highlighted non-structural proteins as "hot-spots". Data analysis supported these findings showing the presence of major hydrophobic sites in the final segment of non-structural protein 1 throughout 2a (Ns2a) and in nonstructural proteins 2b (Ns2b), 4a (Ns4a) and 4b (Ns4b). To our knowledge, these results provide the most comprehensive and detailed snapshot of the immunodominant peptide signature for arbovirus with MHC-class I restriction, which may bring insight into the design of future virus-specific vaccines to arboviruses and for vaccination protocols in highly endemic areas.


Random fiber laser formed by mixing dispersion compensated fiber and single mode fiber.
Taking advantage of relatively strong Rayleigh scattering and Raman gain of dispersion compensated fiber (DCF), three configurations to form efficient random fiber lasers (RFL) are proposed in this paper. Compared with the reported RFL formed by single-mode fiber (SMF) solely, lasing threshold and length of the proposed RFL are effectively reduced through combination of DCF and SMF. In addition, FBGs with central wavelengths at the 1st and 2nd -order Raman Stokes wavelengths are also added to the hybrid SMF/DCF cavity to further reduce the lasing threshold, leading to realization of a new kind of 2nd-order RFL.


Prevalence of and potential influencing factors for alcohol dependence in Europe.
Alcohol use disorders (AUDs), and alcohol dependence (AD) in particular, are prevalent and associated with a large burden of disability and mortality. The aim of this study was to estimate prevalence of AD in the European Union (EU), Iceland, Norway, and Switzerland for the year 2010, and to investigate potential influencing factors. The 1-year prevalence of AD in the EU was estimated at 3.4% among people 18-64 years of age in Europe (women 1.7%, men 5.2%), resulting in close to 11 million affected people. Taking into account all people of all ages, AD, abuse and harmful use resulted in an estimate of 23 million affected people. Prevalence of AD varied widely between European countries, and was significantly impacted by drinking cultures and social norms. Correlations with level of drinking and other drinking variables and with major known outcomes of heavy drinking, such as liver cirrhosis or injury, were moderate. These results suggest a need to rethink the definition of AUDs.


Engraftment of human hematopoietic precursor cells with secondary transfer potential in SCID-hu mice.
Human fetal bone fragments implanted subcutaneously in immunodeficient (SCID) mice maintain active human hematopoiesis. In this study, we show that this human hematopoietic microenvironment supports the engraftment and differentiation of HLA-mismatched, CD34+ primitive hematopoietic progenitor cells isolated from fetal and adult human bone marrow (BM). The BM CD34+ cells were depleted of CD2, CD14, CD15, CD16, glycophorin A, and CD19 lineage-committed cells (CD34+Lin-). Donor cell engraftment was manifested by the presence of B (CD19+) and myeloid (CD33+) cells of donor HLA phenotype. Successful engraftment was observed as early as 4 weeks after fetal BM donor cell injection and sustained for at least 12 weeks, with engraftment success rates of 100% (11/11 grafts) and 92% (11/12 grafts) at 8 and 12 weeks, respectively. Mixed BM chimerism of donor and endogenous cells was consistently observed in SCID-hu bones successfully engrafted with HLA-mismatched CD34+Lin- donor cells. Preconditioning of the SCID-hu bone with a single dose of sublethal (350 rad) whole body irradiation (WBI) immediately before cell injection enhanced the repopulation of the bone grafts with donor cells and, in some instances, resulted in complete repopulation. After WBI, as few as 500 fetal bone marrow CD34+Lin- cells injected in the human bone grafts resulted in donor-derived hematopoiesis. Donor progenitor cells recovered from the SCID-hu bone grafts 8 weeks postinjection had the capacity to repopulate secondary groups of HLA-disparate fetal human bones in SCID-hu mice with B and myeloid cells as well as CD34+ cells in some recipients. In addition, these cells repopulated fetal human thymus fragments in SCID mice with donor thymocytes including immature CD4+CD8+ and mature CD4+CD8- as well as CD4-CD8+ subsets. These results indicate that the fetal human bone implants of SCID-hu mice can support the maintenance of a cell population that has both multilineage potential and repopulating potential for periods of time as long as 16 weeks. The SCID-hu bone model consistently supported the engraftment of both fetal and adult CD34+Lin- cells without the administration of exogenous human cytokines to these animals. This model is currently being used to permit the isolation and characterization of candidate human hematopoietic stem cells (HSCs) and provide important information critical for human HSC therapy in humans.


Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia.
To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P < 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) - including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked - had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00-2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51-1.99). There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome.


An Intelligent Cardiopulmonary Training System and Adherence to Training Intensity: A Feasibility Study.
Objective: Our aim was to evaluate the feasibility of our developed intelligent cardiopulmonary training system (ICTS) and of the percentage of time spent within the target HR range (%time) as an indicator of adherence to training intensity. Methods: In this noncontrolled trial, nine participants with sedentary lifestyles were recruited from the outpatient rehabilitation department of a teaching hospital. All participants received twelve 30 min sessions of cycling ergometer exercises (5 min warm up, 20 min training phase, and 5 min cool down) with the ICTS three times per week. Training intensity was determined at 60−80% heart rate reserve using cardiopulmonary exercise (CPET) pretests. During training, pedaling resistance was automatically adjusted by the ICTS to keep the user's heart rate at the predetermined intensity range. Workload-peak and peak oxygen uptake (VO2-peak) were measured during the pretests and post-tests. We recorded the percentage of time spent within the target heart rate range (%time) during the 20 min training phase for each training session as an indicator of adherence. The correlation between %time and gains in VO2-peak was assessed. Results: After 4 weeks of training on the ICTS, workload-peak and VO2-peak significantly improved by 13.6 ± 7.2 w (mean ± SD, p = 0.008) and 1.5 ± 1.1 mL/kg/min (p = 0.011), respectively. The 12-session average %time ranged from 10.6% to 93.1% among the participants, and five participants achieved an average %time >80%. A positive correlation between average %time and training efficacy was found (rs = 0.85, p = 0.004). Conclusions: Cardiopulmonary training with an ICTS is feasible, and the percentage of time spent within the target heart rate range seems to be a reasonable indicator for monitoring training-intensity adherence.


First Report of Quinoa Downy Mildew Caused by Peronospora variabilis in Republic of Korea.
Quinoa (Chenopodium quinoa Willd.) has become increasingly popular due to its high nutritional value and adaptability to harsh environments. Several field trials have recently been conducted to determine the ability of quinoa cultivars to grow under climate and soil conditions of Republic of Korea. During July 2013, which is the rainy season, plants showing typical symptoms of downy mildew were first observed in an experimental plot in Iksan City, Korea. Infection resulted in small to large, irregular chlorotic areas on the upper leaf surface with a gray mildew developing on the abaxial surface, and often leading to early defoliation. The same symptoms of downy mildew were also found in Pyeongchang County and Imsil County, Korea. A sample from Iksan City was deposited in the Korea University Herbarium (Accession No. KUS-F27388) and used for microscopy and molecular studies. Microscopic examination revealed colorless conidiophores emerging from stomata, straight to slightly curved, 350 to 550 × 10 to 18 μm, and sub-dichotomously branched in 5 to 7 orders. Ultimate branchlets were mostly in pairs, flexuous to curved, 10 to 30 μm long, and had obtuse tips. Conidia were pale brown to olivaceous, broadly ellipsoidal to ellipsoidal, and 25 to 32 × 22 to 25 μm with a length/width ratio of 1.20 to 1.35. These characteristics fit well with Peronospora variabilis, which was previously recorded to be parasitic to C. quinoa and C. album, although P. farinosa f. sp. chenopodii has often been considered a causal agent of downy mildew on quinoa (1). To confirm this morphological identification, amplification and sequencing of the internal transcribed spacer (ITS) region of the rDNA of the Korean specimen were performed using procedures outlined by Choi et al. (1) with oomycete-specific primers DC6 and LR0. The resulting 796-bp sequence was deposited in GenBank (Accession No. KF887493). A comparison with the ITS sequences available in GenBank revealed that it is identical to P. variabilis found on C. album (EF614959, EF614961), and shows only one base pair substitution with another isolates from C. quinoa (EU113305, EU113306). Therefore, the pathogen found in Korea was confirmed to be P. variabilis. Downy mildew is the most damaging disease of quinoa in Argentina, Bolivia, Colombia, Ecuador, and Peru (1). Increasing reports of this disease from India, Canada, the United States, Portugal, and Denmark (2,3,4) have revealed its worldwide occurrence and spread. To our knowledge, this is the first report of a downy mildew on quinoa in Korea (3). It suggests that quinoa downy mildew poses a new and serious threat to production of this crop in Korea. References: (1) Y. J. Choi et al. Mycopathologia 169:403, 2010. (2) S. Danielson et al. Seed Sci. Technol. 32:91, 2004. (3) D. F. Farr and A. Y. Rossman. Fungal Databases. Syst. Mycol. Microbiol. Lab., Online publication, ARS, USDA, Retrieved November 5, 2013. (4) A. L. Testen et al. Plant Dis. 96:146, 2012.


Capsules and virulence in the HAP group of bacteria.
Many species in the genera Haemophilus, Actinobacillus, and Pasteurella produce serotype-specific, negatively-charged, polysaccharide capsules. In pure form, these capsules are nontoxic, relatively inert biologically, and some are poorly immunogenic. The capsule forms the outer-most surface of the bacterium, and prior to the development of specific antibody, inhibits the bactericidal and opsonic activity of normal serum. In contrast, noncapsulated isogenic mutants are generally avirulent, and are quickly cleared by host defenses. In conjunction with the bacterial cell, or through covalent conjugation to a protein carrier, relatively high titers of antibody to capsule can be produced in immunocompetent hosts. For some pathogens (such as H. influenzae type b) antibody to capsule alone is bactericidal, opsonic, and adequate for complete protection against disease. For pathogens that produce potent exotoxins, however, (such as P. haemolytica and A. pleuropneumoniae) antibody to capsule alone may provide only partial protection. The composition or structure of the capsule may also influence the relative virulence of a particular organism. Molecular analysis of the interaction between capsules and host defenses will be required to understand more fully how capsules influence bacterial virulence.


Bioequivalence study of dacomitinib and Vizimpro® in healthy Chinese volunteers under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.
This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their pharmacokinetic (PK) and safety profiles for gaining marketing approval of the new generic drug. A single-center, randomized, open-label, single-dose, two-treatment, two-period, crossover bioequivalence study was conducted in healthy Chinese subjects. Eligible healthy subjects randomly received a single 45 mg dose of test or reference formulations with an administration sequence of test tablet (T), reference tablet (R), or (RT), under both fasting and fed conditions, and each single administration was followed by a 21-day washout period. Plasma concentrations and corresponding non-compartmental PK parameters of dacomitinib were determined. The 90% confidence intervals of the geometric mean ratio (GMR) (test/reference) for Cmax , AUC0-t , and AUC0-∞ , respectively, were 97.75%-119.99%, 101.00%-115.09%, and 100.27%-113.90% under fasting conditions and 95.20%-104.94%, 97.24%-102.23%, and 97.27%-101.88% under fed conditions, which were within the limits of 80%-125%. Under fasting and fed conditions, the PK characteristics of the test dacomitinib tablet and reference Vizimpro® were comparable; the two formulations of dacomitinib were demonstrated to be bioequivalent and well-tolerated in healthy Chinese volunteers.


Single integration and spread of a Copia-like sequence nested in rDNA intergenic spacers of Allium cernuum (Alliaceae).
The 35S ribosomal DNA (rDNA) intergenic spacer (IGS) of Allium cernuum is examined. Initial sequencing of IGS clones revealed that some rDNA units contain a truncated retrotransposon sequence most similar to members of the Copia superfamily. Fluorescence in situ hybridisation (FISH) to metaphase chromosomes indicates that this element is dispersed along both pairs of major rDNA arrays. Southern hybridisation confirmed the presence of this 'relic' Copia-like element in more than 10% of 35S rDNA units, in the same position within the IGS. To measure the intragenomic divergence of the relic retroelement and its flanking sequences amongst different rDNA units, a 1.1-kb region was amplified and cloned. These data collectively point to a single origin for units containing the putative retrotransposon fragment. It is likely that units containing the putative retroelement increased in copy number and dispersed via rDNA homogenisation mechanisms, rather than by multiple retrotransposition events.


Changing ethics in medical practice: a Thai perspective.
The pace of social change in Thailand has seen the rise of various medical services and a global clientele. Currently, medical tourism and cosmetic surgery have an important role in medical practice here. A growing medical market offers a range of services at competitive rates and high levels of efficiency. This essay provides an overview of medical practices in Thailand and their effect on ordinary people.


A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.
Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. ClinicalTrials.gov NCT01856205.


The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K-ATPase and redistribution of apical NHE-3 during acute hypertension.
Acute systolic arterial hypertension provokes a rapid decrease in proximal tubule sodium reabsorption and diuresis associated with inhibition of renal cortex Na,K-ATPase activity and redistribution of apical membrane Na/H exchanger (NHE-3) to heavier density membranes containing markers of intermicrovillar cleft and endosomes. Because cytochrome P-450-dependent arachidonate metabolites participate in the regulation of renal sodium transport and BP, this study tested the hypothesis that these renal responses to acute hypertension would be prevented if cytochrome P-450 metabolism were inhibited by cobalt chloride (CoCl2). Four groups of rats (n = 4 to 5) were studied: (1) sham-operated; (2) 50 mg of CoCl2/kg subcutaneously for 2 d; (3) acute hypertension by constricting arteries for 5 min; and (4) acute hypertension after CoCl2 treatment as in group 3. Renal cortex was analyzed after sorbitol density gradient fractionation. CoCl2 treatment alone did not significantly affect the rate of urine output, endogenous lithium clearance (an inverse measure of proximal tubule sodium reabsorption), maximal activity of Na,K-ATPase, or subcellular distribution of NHE-3-containing membranes. In non-CoCl2-treated animals, acute hypertension provoked a three- to fourfold increase in urine output and endogenous lithium clearance, 33% inhibition of renal cortex Na,K-ATPase activity, and redistribution of NHE-3 out of the apical membrane peak. In CoCl2-treated animals, acute urine output and endogenous lithium clearance increased only twofold during acute hypertension, there was no inhibition of Na,K-ATPase activity, and there was no redistribution of NHE-3 immunoreactivity to higher density membranes. These findings demonstrate that CoCl2 treatment both attenuates the inhibition of proximal tubule sodium reabsorption and diuresis and abolishes Na,K-ATPase inhibition and NHE-3 redistribution during acute hypertension, evidence that these responses may be mediated by cytochrome P-450 arachidonate metabolites.


Complex pathways and memory in compressed corrugated sheets.
The nonlinear response of driven complex materials-disordered magnets, amorphous media, and crumpled sheets-features intricate transition pathways where the system repeatedly hops between metastable states. Such pathways encode memory effects and may allow information processing, yet tools are lacking to experimentally observe and control these pathways, and their full breadth has not been explored. Here we introduce compression of corrugated elastic sheets to precisely observe and manipulate their full, multistep pathways, which are reproducible, robust, and controlled by geometry. We show how manipulation of the boundaries allows us to elicit multiple targeted pathways from a single sample. In all cases, each state in the pathway can be encoded by the binary state of material bits called hysterons, and the strength of their interactions plays a crucial role. In particular, as function of increasing interaction strength, we observe Preisach pathways, expected in systems of independently switching hysterons; scrambled pathways that evidence hitherto unexplored interactions between these material bits; and accumulator pathways which leverage these interactions to perform an elementary computation. Our work opens a route to probe, manipulate, and understand complex pathways, impacting future applications in soft robotics and information processing in materials.


Renal interstitial hydrostatic pressure during verapamil-induced natriuresis.
Infusion of calcium antagonists results in significant increases in sodium excretion, an effect that is exacerbated in hypertensive animals. The mechanism responsible for the increase in sodium excretion has not been elucidated. The purpose of this study was to determine the role of renal interstitial hydrostatic pressure (RIHP) in mediating increases in sodium excretion produced by the calcium antagonist verapamil. Changes in renal hemodynamics and electrolyte excretion were examined in response to an intrarenal infusion of verapamil (100 micrograms/min) in normal dogs and in dogs with angiotensin II-induced hypertension. Infusion of verapamil in normal dogs increased renal blood flow by 18% and had no effect on glomerular filtration rate. Renal vascular resistance and filtration fraction both decreased in response to verapamil. Absolute (5.1 +/- 2.3 to 176 +/- 45.8 mueq/min) and fractional excretion of sodium (0.21 +/- 0.13 to 7.36 +/- 3.12%) also increased significantly. Despite renal vasodilation, the natriuresis was not associated with significant increases in RIHP (6.4 +/- 0.9 to 5.8 +/- 0.9 mmHg). Infusion of verapamil into dogs with angiotensin II hypertension resulted in a natriuresis (4.2 +/- 1.6 to 338.7 +/- 78.3 mueq/min) that was much greater than under normal conditions. Although the renal vasodilation was significantly higher in the angiotensin II-hypertensive dogs, the enhanced natriuresis in these animals was not associated with increases in RIHP. The results of this study indicate that increases in RIHP are not responsible for the natriuresis produced by verapamil in normal or angiotensin II-hypertensive dogs.


Lesions of the dorsomedial striatum impair formation of attentional set in rats.
Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies. Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex. The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting. Rats were tested in two set-shifting tasks following quinolinic acid injections bilaterally into the DMS. When tested in a rodent version of the set-shifting task, rats with a DMS lesion displayed a greater number of errors during the reversal stages of the task than sham lesion controls but the nature of the errors did not differ between the two groups. Interestingly, when the rats were tested in a modified version of the set-shifting task, directly designed for measuring the formation of an attentional set, sham lesion controls displayed a pronounced shift-cost, evident of successful set-formation. In contrast, rats with DMS lesions failed to form an attentional set, showing no performance cost when a shift of attention was required. These results support previous reports of the importance of the DMS in behavioural flexibility but also suggest that this region is vital for the formation of set, possibly by extrapolating different perceptions into a unified representation of a dimension.


Early and mid-term outcomes of percutaneous mitral valve repair with the MitraClip®: comparative analysis of different EuroSCORE strata.
Compare mid-term outcomes after MitraClip® implantation for severe mitral regurgitation (MR) in patients categorised in different logistic EuroSCORE (LES) groups. MitraClip was implanted in 85 patients (78 ± 6 years, 48 men [56.5%]) with severe symptomatic MR. Baseline characteristics, perioperative results, mid-term survival, major adverse cerebrovascular and cardiac events (MACCE), and re-hospitalisation were compared in patients with LES <20% (n=30) and ≥ 20% (n=55). Overall LES was 24 ± 12 (range 2.5-56.3) and STS-score 12 ± 7 (range 1.2-31.2). Overall procedural success rate was 96.5% with an in-hospital mortality rate of 3.5%. Echocardiographic and clinical follow-up confirmed similar mean transmitral pressure gradient (p=0.13), MR degree (p=0.48), and NYHA Class (p=0.93). Estimated six-month survival and freedom from composite endpoint was 80.7%/77.1% in LES ≥ 20% and 90.8/86.6% in LES<20% group, respectively (p= 0.014; p=0.018). Multivariate analysis determined LES ≥ 20% (OR=8.1; 95% CI 1.002-65.186), mean transmitral gradient after intervention (OR 2.5; 95% CI 1.267-5.131) and residual MR (OR=5.1; 95% CI 1.464-17.946) as predictors for overall mortality. LES is a good predictor of perioperative results, and follow-up adverse outcomes after MitraClip implantation are significantly influenced by the preoperative risk profile. The presence of residual MR immediately after MitraClip therapy can exacerbate the occurrence of MACCE.


Curcumin promotes apoptosis of human melanoma cells by caspase 3.
Cutaneous melanoma (CM) is a malignant neoplasm with a high metastatic rate that shows poor response to systemic treatments in patients with advanced stages. Recently, studies have highlighted the antineoplastic potential of natural compounds, such as polyphenols, in the adjuvant therapy context to treat CM. The objective of the present study was to evaluate the effect of different concentrations of curcumin (0.1-100 µM) on the metastatic CM cell line SK-MEL-28. The cells were treated for 6 and 24 h with different concentrations of curcumin. Cell viability was assessed by 3-(4,5-dimethyl-2thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and fluorescence microscopy. The apoptotic-inducing potential was detected by annexin V flow cytometry. The wound healing assay was used to verify cell migration after the curcumin exposition. The redox profile was evaluated by levels of the pro-oxidant markers reactive oxygen species (ROS) and Nitric oxide (NOx) and antioxidants of total thiols (PSH) and nonprotein thiols. The gene expression and enzymatic activity of caspase 3 were evaluated by reverse transcription-quantitative polymerase chain reaction and a sensitive fluorescence assay, respectively. Curcumin significantly decreased the cell viability of SK-MEL-28 cells at both exposure times. It also induced apoptosis at the highest concentration tested (p < .0001). SK-MEL-28 cell migration was inhibited by curcumin after treatment with 10 µM (p < .0001) and 100 µM (p < .0001) for 6 and 24 h (p = .0006 and p < .0001, respectively). Furthermore, curcumin significantly increased levels of ROS and NOx. Finally, curcumin was capable of increasing the gene expression at 10 µM (p = .0344) and 100 µM (p = .0067) and enzymatic activity at 10 µM (p = .0086) and 100 µM (p < .0001) of caspase 3 after 24 h. For the first time, we elucidated in our study that curcumin increases ROS levels, promoting oxidative stress that activates the caspase pathway and culminates in SK-MEL-28 metastatic CM cell death.


Spatial analysis of the prevalence of schistosomiasis in an endemic coastal area in north-eastern Brazil.
Due to contact and misuse of water drainage channels, schistosomiasis has spread and become a constant concern in northeastern Brazil. The aim of this study was to monitor human cases of Schistosomiasis mansoni and the breeding areas of the snail intermediate host Biomphalaria glabrata through spatial analysis in a community named Invasão do Canal do Guaxinim, located in Barra dos Coqueiros City in an endemic coastal part of the state of Sergipe, Brazil. This research was performed as a cross-sectional epidemiological study conducted with parasitological and malacological surveys. To verify the spatial analysis, a two-year spatial point pattern analysis was performed by means of Kernel intensity estimation using TerraView software 4.2.2. A schistosomiasis prevalence reduction from 8.1% (2013) to 4.9% (2014) was observed but mild infection prevailed in adolescents and/or young adults during the two-year study. In malacological research, 387 specimens of snails of the genus B. glabrata were collected and all were negative with regard to schistosomiasis. Spatial analysis showed a strong, spatial trend of increased transmission risk areas north and south of the community, both in 2013 and 2014. In Invasão do Canal do Guaxinim itself, the increased risk was only seen in the northern part. When combined, the human and the malacological spatial analyses constituted an important methodological approach for monitoring and controlling this parasitic disease.


Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy.
Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD. Two piglets were obtained after embryo transfer, one of piglets was identified as DMD-modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD-modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD-modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig.


Use of total internal reflection Raman (TIR) and attenuated total reflection infrared (ATR-IR) spectroscopy to analyze component separation in thin offset ink films after setting on coated paper surfaces.
The interactive behavior of ink constituents with porous substrates during and after the offset print process has an important effect on the quality of printed products. To help elucidate the distribution of ink components between the retained ink layer and the substrate, a variety of spectroscopic and microscopic analysis techniques have been developed. This paper describes for the first time the use of total internal reflection (TIR) Raman spectroscopy to analyze the penetration behavior of separated offset ink components (linseed oil, solid color pigment) in coated papers providing chemically intrinsic information rapidly, nondestructively, and with minimal sample preparation. In addition, the already widely applied technique of attenuated total reflection infrared spectroscopy (ATR-IR) was evaluated in parallel and compared. The results of the ATR-IR Raman clearly revealed an improvement in uppermost depth resolution compared with values previously published from other nondestructive techniques, and the method is shown to be capable of providing new knowledge of the setting of thin (0.25-2 μm) offset ink films, allowing the spreading and the penetration behavior on physically different paper coating surfaces to be studied.


Detecting genes for variation in parasite burden and immunological traits in a wild population: testing the candidate gene approach.
Identifying the genes underlying phenotypic variation in natural populations can provide novel insight into the evolutionary process. The candidate gene approach has been applied to studies of a number of traits in various species, in an attempt to elucidate their genetic basis. Here, we test the application of the candidate gene approach to identify the loci involved in variation in gastrointestinal parasite burden, a complex trait likely to be controlled by many loci, in a wild population of Soay sheep. A comprehensive literature review, Gene Ontology databases, and comparative genomics resources between cattle and sheep were used to generate a list of candidate genes. In a pilot study, these candidates, along with 50 random genes, were then sequenced in two pools of Soay sheep; one with low gastrointestinal nematode burden and the other high, using a NimbleGen sequence capture experiment. Further candidates were identified from single nucleotide polymorphisms (SNPs) that were highly differentiated between high- and low-resistance sheep breeds. A panel of 192 candidate and control SNPs were then typed in 960 individual Soay sheep to examine whether they individually explained variation in parasite burden, as measured as faecal egg count, as well as two immune measures (Teladorsagia circumcincta-specific antibodies and antinuclear antibodies). The cumulative effect of the candidate and control SNPs were estimated by fitting genetic relationship matrices (GRMs) as random effects in animal models of the three traits. No more significant SNPs were identified in the pilot sequencing experiment and association study than expected by chance. Furthermore, no significant difference was found between the proportions of candidate or control SNPs that were found to be significantly associated with parasite burden/immune measures. No significant effect of the candidate or control gene GRMs was found. There is thus little support for the candidate gene approach to the identification of loci explaining variation in parasitological and immunological traits in this population. However, a number of SNPs explained significant variation in multiple traits and significant correlations were found between the proportions of variance explained by individual SNPs across multiple traits. The significant SNPs identified in this study may still, therefore, merit further investigation.


Mass gathering medicine: a predictive model for patient presentation and transport rates.
This paper reports on research into the influence of environmental factors (including crowd size, temperature, humidity, and venue type) on the number of patients and the patient problems presenting to first-aid services at large, public events in Australia. Regression models were developed to predict rates of patient presentation and of transportation-to-a-hospital for future mass gatherings. To develop a data set and predictive model that can be applied across venues and types of mass gathering events that is not venue or event specific. Data collected will allow informed event planning for future mass gatherings for which health care services are required. Mass gatherings were defined as public events attended by in excess of 25,000 people. Over a period of 12 months, 201 mass gatherings attended by a combined audience in excess of 12 million people were surveyed throughout Australia. The survey was undertaken by St. John Ambulance Australia personnel. The researchers collected data on the incidence and type of patients presenting for treatment and on the environmental factors that may influence these presentations. A standard reporting format and definition of event geography was employed to overcome the event-specific nature of many previous surveys. There are 11,956 patients in the sample. The patient presentation rate across all event types was 0.992/1,000 attendees, and the transportation-to-hospital rate was 0.027/1,000 persons in attendance. The rates of patient presentations declined slightly as crowd sizes increased. The weather (particularly the relative humidity) was related positively to an increase in the rates of presentations. Other factors that influenced the number and type of patients presenting were the mobility of the crowd, the availability of alcohol, the event being enclosed by a boundary, and the number of patient-care personnel on duty. Three regression models were developed to predict presentation rates at future events. Several features of the event environment influence patient presentation rates, and that the prediction of patient load at these events is complex and multifactorial. The use of regression modeling and close attention to existing historical data for an event can improve planning and the provision of health care services at mass gatherings.


Alteration of A549 carcinoma cell protein synthesis profile induced by lung cancer patient serum.
Several elements such as circulating DNA and metastatic cells, containing the same primary tumor mutations, oncogenic proteins, cytokines, and other tumor related not yet identified factors, can be found in the blood stream of cancer patients. In this study we have shown that serum factors presented in lung cancer patients can modify the protein profile of the lung adenocarcinoma cell line (A549). This alteration in cellular protein profile can be an important event in the cell phenotype modification necessary for the advance of the disease. There have been no similar studies regarding cancer cell protein synthesis induction by human cancer serum.


The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding.
Serotonergic dysfunction is implicated in the pathogenesis of posttraumatic stress disorder (PTSD), and recent animal models suggest that disturbances in serotonin type 1B receptor function, in particular, may contribute to chronic anxiety. However, the specific role of the serotonin type 1B receptor has not been studied in patients with PTSD. To investigate in vivo serotonin type 1B receptor expression in individuals with PTSD, trauma-exposed control participants without PTSD (TC), and healthy (non-trauma-exposed) control participants (HC) using positron emission tomography and the recently developed serotonin type 1B receptor selective radiotracer [(11)C]P943. Cross-sectional positron emission tomography study under resting conditions. Academic and Veterans Affairs medical centers. Ninety-six individuals in 3 study groups: PTSD (n = 49), TC (n = 20), and HC (n = 27). Main Outcome Measure Regional [(11)C]P943 binding potential (BP(ND)) values in an a priori-defined limbic corticostriatal circuit investigated using multivariate analysis of variance and multiple regression analysis. A history of severe trauma exposure in the PTSD and TC groups was associated with marked reductions in [(11)C]P943 BP(ND) in the caudate, the amygdala, and the anterior cingulate cortex. Participant age at first trauma exposure was strongly associated with low [(11)C]P943 BP(ND). Developmentally earlier trauma exposure also was associated with greater PTSD symptom severity and major depression comorbidity. These data suggest an enduring effect of trauma history on brain function and the phenotype of PTSD. The association of early age at first trauma and more pronounced neurobiological and behavioral alterations in PTSD suggests a developmental component in the cause of PTSD.


Development and Reliability of the Functional Evaluation Scale for Duchenne Muscular Dystrophy, Gait Domain: A Pilot Study.
The progression of Duchenne muscular dystrophy (DMD) results in the emergence of multiple and varied synergies to compensate muscle weakness and to deal with the demands of the functional tasks (e.g. gait). No functional evaluation instrument for individuals with DMD allows the detailed description (subjective qualitative evaluation) and compensatory movement scoring (objective quantitative evaluation) exclusively of gait. For this reason, clinicians and therapists face difficulties in assessment and decision-making of this functional activity. This study aimed to elaborate the gait domain of the Functional Evaluation Scale for DMD (FES-DMD-GD) and test its intra-rater and inter-rater reliabilities and its relationship with age and timed motor performance. We listed all the compensatory movements observed in 102 10-m gait videos of 51 children with DMD. Based on this report, the FES-DMD-GD was created and submitted to the review of 10 experts. After incorporating the experts suggestions, three examiners scored the videos using the FES-DMD-GD. The intra-rater and inter-rater reliabilities was calculated. Spearman correlation tests investigated the relationships between FES-DMD-GD and age and timed motor performance (p < 0.05). The FES-DMD-GD was composed of three phases and had 14 items to quantify compensatory movements on gait. Intra-class correlation coefficients ranged from acceptable (0.74) to excellent (0.99). FES-DMD-GD correlated to age and timed motor performance. This pilot version of FES-DMD-GD showed reliability and correlated to age and timed motor performance.


High-throughput sequencing reveals the change of TCR α chain CDR3 with Takayasu arteritis.
Takayasu arteritis (TAK) is an inflammatory disease of blood vessels, and its pathogenesis is not clear at present. In this study, we explored the immunological characteristics of T cell receptor (TCR) α-chain complementarity-determining region 3 (CDR3) in patients with TAK. Five untreated patients with TAK were collected from June 2019 to December 2019. Four healthy blood samples were matched as the control group. The blood mononuclear cells were separated, and RNA was extracted for reverse transcription to obtain complementary DNA. Then high-throughput sequencing was performed. The quality of samples was evaluated by principal component analysis. We compared the diversity and expression of TCR α-chain between TAK group and control group. R software was used for statistical analysis and drawing, and Mann-Whitney U test was used to analyze the differences between the two groups. The results showed that there was a significant difference in the diversity of TCR α-chain CDR3 between the two groups. Three V region genes expression significantly higher in the TAK patients than in the control group. A total of 196 VJ rearrangement genes are significantly different between the two groups, of which 149 rearrangement genes in the TAK group are lower than those in the control group, and 47 rearrangement genes in the TAK group are higher than those in the control group. Patients with TAK have a unique TCR α-chain CDR3 library. These characteristic genes may be a marker for early diagnosis and provide a new theoretical basis for treating TAK.


A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS.
Both didanosine and zalcitabine are commonly used to treat patients with human immunodeficiency virus (HIV) infection who cannot tolerate zidovudine treatment or who have had disease progression despite it. The relative efficacy and safety of these second-line therapies are not well defined. In this multicenter, open-label trial we randomly assigned 467 patients who previously received zidovudine and had 300 or fewer CD4 cells per cubic millimeter or a diagnosis of the acquired immunodeficiency syndrome (AIDS) to treatment with either didanosine (500 mg per day) or zalcitabine (2.25 mg per day). After a median follow-up of 16 months, disease progression or death occurred in 157 of 230 patients assigned to didanosine and 152 of 237 patients assigned to zalcitabine, for a relative risk of 0.93 for the zalcitabine group as compared with the didanosine group (P = 0.56), which decreased to 0.84 (P = 0.15) after adjustment for the CD4 count, Karnofsky score, and presence of AIDS at base line. There were 100 deaths in the didanosine group and 88 in the zalcitabine group, for a relative risk of 0.78 (P = 0.09) and an adjusted relative risk of 0.63 (P = 0.003). A majority of patients in each group (66 percent) had at least one adverse event during treatment (153 patients taking didanosine and 157 taking zalcitabine). Peripheral neuropathy and stomatitis occurred more often with zalcitabine and diarrhea and abdominal pain more frequently with didanosine. For patients with HIV infection who have not responded to treatment with zidovudine, zalcitabine is at least as efficacious as didanosine in delaying disease progression and death.


Surgical endodontic reintervention using a modern technique: 2 case reports.
Management of post-treatment apical periodontitis after surgery--assuming the tooth is restorable, periodontally sound, and the patient desires to retain it--includes nonsurgical retreatment and surgical reintervention. This article presents 2 cases of surgical reintervention using a modern surgery technique that utilized an operating microscope, ultrasonic tips, and biocompatible materials. After the reinterventions were performed, adequate periradicular healing was observed in both cases. These cases reinforce the precept that combining knowledge about the biologic aspects of endodontics with surgical endodontic treatment using a modern technique is a predictable treatment option.


Lifetime of major histocompatibility complex class-I membrane clusters is controlled by the actin cytoskeleton.
Lateral heterogeneity of cell membranes has been demonstrated in numerous studies showing anomalous diffusion of membrane proteins; it has been explained by models and experiments suggesting dynamic barriers to free diffusion, that temporarily confine membrane proteins into microscopic patches. This picture, however, comes short of explaining a steady-state patchy distribution of proteins, in face of the transient opening of the barriers. In our previous work we directly imaged persistent clusters of MHC-I, a type I transmembrane protein, and proposed a model of a dynamic equilibrium between proteins newly delivered to the cell surface by vesicle traffic, temporary confinement by dynamic barriers to lateral diffusion, and dispersion of the clusters by diffusion over the dynamic barriers. Our model predicted that the clusters are dynamic, appearing when an exocytic vesicle fuses with the plasma membrane and dispersing with a typical lifetime that depends on lateral diffusion and the dynamics of barriers. In a subsequent work, we showed this to be the case. Here we test another prediction of the model, and show that changing the stability of actin barriers to lateral diffusion changes cluster lifetimes. We also develop a model for the distribution of cluster lifetimes, consistent with the function of barriers to lateral diffusion in maintaining MHC-I clusters.


Optimization of cholesterol removal by probiotics in the presence of prebiotics by using a response surface method.
Lactobacillus casei ASCC 292 was grown in the presence of six prebiotics, namely, sorbitol, mannitol, maltodextrin, high-amylose maize, fructooligosaccharide (FOS), and inulin, in order to determine the combination of probiotic and prebiotics that would remove the highest level of cholesterol. A first-order model showed that the combination of L. casei ASCC 292, FOS, and maltodextrin was the most efficient for the removal of cholesterol, and the optimum experimental region was developed by using the steepest ascent. This led to the middle points of probiotic (1.70% [wt/vol]), FOS (4.80% [wt/vol]), and maltodextrin (6.80% [wt/vol]) for the development of a central composite design for optimization. Perturbation plot, response surface, and coefficient estimates showed that all three factors had significant quadratic effects on cholesterol removal, with FOS showing the most conspicuous quadratic change. A second-order polynomial regression model estimated that the optimum condition of the factors for cholesterol removal by L. casei ASCC 292 is 1.71% (wt/vol) probiotic, 4.95% (wt/vol) FOS, and 6.62% (wt/vol) maltodextrin. Validation experiments showed that the predicted optimum conditions were more efficient than the high and low levels of the factors and the center points. A response surface method proved reliable for developing the model, optimizing factors, and analyzing interaction effects. Analyses of growth, substrate utilization, growth yield, mean doubling time, and short-chain fatty acid (SCFA) production by the use of quadratic models indicated that cholesterol removal was growth associated. The concentration of L. casei ASCC 292 had the most significant quadratic effect on all responses studied, except for substrate utilization and SCFA production, which were significantly (P < 0.05) influenced by the interactions between the probiotic and both prebiotics, indicating that they were closely associated with the uptake of prebiotics.


Genome-wide identification of invertases in Fabaceae, focusing on transcriptional regulation of Pisum sativum invertases in seed subjected to drought.
Invertases are key enzymes for carbon metabolism, cleaving sucrose into energy-rich and signaling metabolites, glucose and fructose. Invertases play pivotal roles in development and stress response, determining yield and quality of seed production. In this context, the repertoire of invertase gene families is critically scarce in legumes. Here, we performed a systematic search for invertase families in 16 Fabaceae genomes. For instance, we identified 19 invertase genes in the model plant Medicago and 17 accessions in the agronomic crop Pisum sativum. Our comprehensive phylogenetic analysis sets a milestone for the scientific community as we propose a new nomenclature to correctly name plant invertases. Thus, neutral invertases were classified into four clades of cytosolic invertase (CINV). Acid invertases were classified into two cell wall invertase clades (CWINV) and two vacuolar invertase clades (VINV). Then, we explored transcriptional regulation of the pea invertase family, focusing on seed development and water stress. Invertase expression decreased sharply from embryogenesis to seed-filling stages, consistent with higher sucrose and lower monosaccharide contents. The vacuolar invertase PsVINV1.1 clearly marked the transition between both developmental stages. We hypothesize that the predominantly expressed cell wall invertase, PsCWINV1.2, may drive sucrose unloading towards developing seeds. The same candidates, PsVINV1.1 and PsCWINV1.2, were also regulated by water deficit during embryonic stage. We suggest that PsVINV1.1 along with vacuolar sugar transporters maintain cellular osmotic pressure and PsCWINV1.2 control hexose provision, thereby ensuring embryo survival in drought conditions. Altogether, our findings provide novel insights into the regulation of plant carbon metabolism in a challenging environment.