Consistency evaluation of values of weight, height, and body mass index in Food Intake and Physical Activity of School Children: the quality control of data entry in the computerized system.
The quality control of data entry in computerized questionnaires is an important step in the validation of new instruments. The study assessed the consistency of recorded weight and height on the Food Intake and Physical Activity of School Children (Web-CAAFE) between repeated measures and against directly measured data. Students from the 2nd to the 5th grade (n = 390) had their weight and height directly measured and then filled out the Web-CAAFE. A subsample (n = 92) filled out the Web-CAAFE twice, three hours apart. The analysis included hierarchical linear regression, mixed linear regression model, to evaluate the bias, and intraclass correlation coefficient (ICC), to assess consistency. Univariate linear regression assessed the effect of gender, reading/writing performance, and computer/internet use and possession on residuals of fixed and random effects. The Web-CAAFE showed high values of ICC between repeated measures (body weight = 0.996, height = 0.937, body mass index - BMI = 0.972), and regarding the checked measures (body weight = 0.962, height = 0.882, BMI = 0.828). The difference between means of body weight, height, and BMI directly measured and recorded was 208 g, -2 mm, and 0.238 kg/m², respectively, indicating slight BMI underestimation due to underestimation of weight and overestimation of height. This trend was related to body weight and age. Height and weight data entered in the Web-CAAFE by children were highly correlated with direct measurements and with the repeated entry. The bias found was similar to validation studies of self-reported weight and height in comparison to direct measurements.


Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction.
Chronic increases in blood flow increase arterial diameter and NO-dependent dilation in resistance arteries. Because endothelial dysfunction accompanies metabolic syndrome, we hypothesized that flow-mediated remodeling might be impaired in obese rat resistance arteries. Obese and lean Zucker rat mesenteric resistance arteries were exposed to chronic flow increases through arterial ligation in vivo: arteries exposed to high flow were compared with normal flow arteries. Diameter was measured in vitro in cannulated arteries using pressure arteriography. After 7 days, outward remodeling (diameter increased from 346+/-9 to 412+/-11 mum at 100 mm Hg) occurred in lean high-flow arteries. Endothelium-dependent tone was reduced in high-flow arteries from obese rats by contrast with lean animals. On the other hand, diameter enlargement occurred similarly in the 2 strains. The involvement of NO in endothelium-dependent dilation (evidenced by NO blockade) and endothelial NO synthase phosphorylation was smaller in obese than in lean rats. Superoxide anion and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression (p67phox and gp91phox) increased in obese rats and were higher in high-flow than in control arteries. Acute Tempol (a catalase mimetic), catalase plus superoxide dismutase, and l-arginine plus tetrahydrobiopterin restored endothelium-dependent dilation in obese rat normal and high-flow arteries to the level found in lean control arteries. Thus, flow-induced remodeling in obese resistance arteries was associated with a reduced endothelium-mediated dilation because of a decreased NO bioavailability and an excessive superoxide production. This dysfunction might have negative consequences in ischemic diseases in patients with obesity or metabolic syndrome.


Exercise and hypertrophic cardiomyopathy: Two incompatible entities?
A greater understanding of the pathogenic mechanisms underpinning hypertrophic cardiomyopathy (HCM) has translated to improved medical care and better survival of affected individuals. Historically these patients were considered to be at high risk of sudden cardiac death (SCD) during exercise; therefore, exercise recommendations were highly conservative and promoted a sedentary life style. There is emerging evidence that suggests that exercise in HCM has a favorable effect on cardiovascular remodeling and moderate exercise programs have not raised any safety concerns. Furthermore, individuals with HCM have a similar burden of atherosclerotic risk factors as the general population in whom exercise has been associated with a reduction in myocardial infarction, stroke, and heart failure, especially among those with a high-risk burden. Small studies revealed that athletes who choose to continue with regular competition do not demonstrate adverse outcomes when compared to those who discontinue sport, and active individuals implanted with an implantable cardioverter defibrillator do not have an increased risk of appropriate shocks or other adverse events. The recently published exercise recommendations from the European Association for Preventative Cardiology account for more contemporary evidence and adopt a more liberal stance regarding competitive and high intensity sport in individuals with low-risk HCM. This review addresses the issue of exercise in individuals with HCM, and explores current evidence supporting safety of exercise in HCM, potential caveats, and areas of further research.


Role of blood-oxygen transport in thermal tolerance of the cuttlefish, Sepia officinalis.
Mechanisms that affect thermal tolerance of ectothermic organisms have recently received much interest, mainly due to global warming and climate-change debates in both the public and in the scientific community. In physiological terms, thermal tolerance of several marine ectothermic taxa can be linked to oxygen availability, with capacity limitations in ventilatory and circulatory systems contributing to oxygen limitation at extreme temperatures. The present review briefly summarizes the processes that define thermal tolerance in a model cephalopod organism, the cuttlefish Sepia officinalis, with a focus on the contribution of the cephalopod oxygen-carrying blood pigment, hemocyanin. When acutely exposed to either extremely high or low temperatures, cuttlefish display a gradual transition to an anaerobic mode of energy production in key muscle tissues once critical temperatures (T(crit)) are reached. At high temperatures, stagnating metabolic rates and a developing hypoxemia can be correlated with a progressive failure of the circulatory system, well before T(crit) is reached. However, at low temperatures, declining metabolic rates cannot be related to ventilatory or circulatory failure. Rather, we propose a role for hemocyanin functional characteristics as a major limiting factor preventing proper tissue oxygenation. Using information on the oxygen binding characteristics of cephalopod hemocyanins, we argue that high oxygen affinities (= low P(50) values), as found at low temperatures, allow efficient oxygen shuttling only at very low venous oxygen partial pressures. Low venous PO(2)s limit rates of oxygen diffusion into cells, thus eventually causing the observed transition to anaerobic metabolism. On the basis of existing blood physiological, molecular, and crystallographical data, the potential to resolve the role of hemocyanin isoforms in thermal adaptation by an integrated molecular physiological approach is discussed.


Simple method for determination of the number of Helicobacter pylori CagA variable-region EPIYA tyrosine phosphorylation motifs by PCR.
Helicobacter pylori strains possessing the cag pathogenicity island are associated with the development of gastric cancer. The CagA protein is translocated into epithelial cells and becomes phosphorylated on tyrosine residues within EPIYA motifs, which may be repeated within the variable region of the protein. Strains possessing CagA with greater numbers of these repeats have been more closely associated with gastric carcinogenesis. Phosphorylated CagA leads to epithelial cell elongation, which is dependent on the number of variable-region EPIYA motifs. Thus, determination of the degree of CagA phosphorylation and the number of EPIYA motifs appears to be more important than detection of cagA alone. Determination of the number of EPIYA motifs by nucleotide sequencing, however, is a laborious and expensive process. We describe here a novel and rapid PCR method for determination of the pattern of repeats containing the EPIYA motif. This will aid in the identification of those strains that may be more likely to cause disease.


Renal biopsy in a patient with haemophilia A and cryoglobulinaemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection.
A renal biopsy was performed in a 47-year-old man with haemophilia A. Thirty minutes after administration of an intravenous bolus of 4000 units of recombinant factor VIII, which increased the activity to 74-91%, a needle renal biopsy was successfully performed, followed by administration of 3000 units of factor VIII in the evening, and then the subsequent morning and evening. The patient was diagnosed with hepatitis C virus-associated membranoproliferative glomerulonephritis. Treatment with interferon, ribavirin, prednisolone and cyclosporine A improved the nephrotic syndrome. This is the first report of a successful renal biopsy in a patient with haemophilia A after factor VIII injection.


Which Protocol is better for Treatment of Ectopic Pregnancy by Methotrexate? Single-dose or Multiple-dose.
Ectopic pregnancy (EP) is the most common cause of death in the first trimester of pregnancy. Methotrexate (MTX) is an acceptable treatment in the cases with the lack of tube rupture or no important one, which has reduced surgical treatment. Despite numerous studies, there is still no consensus about medications. The present study is aimed to evaluate the single- and multiple-dose of MTX among these patients. This clinical trial study was done on 108 EP patients who were selected for the systemic MTX treatment and divided into two groups. For the single-dose group, MTX was administered once and β human chorionic gonadotropin (βHCG) levels were measured first and then on days 4 and 7. In the multi-dose group, 1 mg/kg MTX was injected on days 1, 3, 5, and 7. In both groups, MTX was prescribed following these days if βHCG was not reduced. In the two groups, βHCG levels were assessed after 1 week. The success rate of treatment and complications were followed up and recorded up to 6 weeks after treatment. The success rate in the single-dose and multiple-dose MTX group was 47% and 51%. The MTX level in the single dose group decreased from 2532 ± 1154 mIU/mL to 1341 ± 553 mIU/mL and in the multiple dose group from 2671 ± 2685 mIU/mL to 1313 ± 605 mIU/mL (P < 0.05). Although a significant decrease was observed in each of the two groups over time, no significant difference was found between the two groups (P > 0.05). Single and multi-dose regimen did not show a significant difference in terms of the success of treatment. Therefore, given that the lower dose of the drug associated with lower the risk of complications, it is safe to choose the single-dose regimen.


Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.
To compare the prevalence of cardiovascular diseases and their risk factors between patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and control subjects. Data for patients continuously enrolled in an integrated outcomes database between January 1, 2001, and December 31, 2002, with International Classification of Diseases, 9th Revision codes of 714.x (RA), 696.0 (PsA), or 720.0 (AS) were evaluated in this cross-sectional comparative study. Control groups were established for each patient group (1:4 ratio) by matching on the basis of age, sex, geographic region, and length of time in plan. Age- and sex-adjusted prevalence of cardiovascular comorbidities and risk factors were calculated; the prevalence ratio of the comorbidities and risk factors for the patient groups compared with the control population were estimated. Use of selected cardiovascular medications was also compared between patient and control groups. The RA, PsA, and AS cohorts comprised 28,208, 3066, and 1843 patients, respectively. The prevalence ratio of ischemic heart disease (1.5, 1.3, 1.2), atherosclerosis (1.9, 1.4, 1.5), peripheral vascular disease (2.4, 1.6, 1.6), congestive heart failure (2.0, 1.5, 1.8), cerebrovascular disease (1.6, 1.3, 1.7), type II diabetes (1.4, 1.5, 1.2), hyperlipidemia (1.2, 1.2, 1.2), and hypertension (1.3, 1.3, 1.3) were higher in patients than controls. For RA, PsA, and AS, use of angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, nitrates/vasodilators, anticoagulants, and antihyperlipidemia agents was significantly higher in patients than controls. Cardiovascular diseases and their risk factors were more common in patients with RA, PsA, and AS than in matched controls.


Talking theory of mind talk: young school-aged children's everyday conversation and understanding of mind and emotion.
Links between young children's everyday use of mindful conversational skills and their success on laboratory tests of theory of mind understanding (ToM) were evaluated. Using published scales, teachers rated the conversational behavior and shyness of 129 children aged 60 to 101 months (M = 78·8 months) who were in their first years of primary school. The children also took batteries of first- and second-order false-belief tests along with tests of emotion understanding and general language ability. Correlational and regression analyses showed that performance on false-belief tests of ToM significantly predicted children's competence at reading others' minds in their everyday conversational interactions. Furthermore, these links transcended individual differences in language ability, shy personality, emotion understanding, and age. These findings augment and extend a growing body of evidence linking performance on laboratory ToM tests to socially competent real-world behavior.


Infectious salmon anaemia virus (ISAV) isolates induce distinct gene expression responses in the Atlantic salmon (Salmo salar) macrophage/dendritic-like cell line TO, assessed using genomic techniques.
Infectious salmon anaemia virus (ISAV) is a marine orthomyxovirus of significant interest not only as a cause of a fatal disease of farmed Atlantic salmon resulting in severe economic losses to the aquaculture industry, but also as the only poikilothermic orthomyxovirus. ISAV targets vascular endothelial cells and macrophages, and is known to influence the expression of both innate and adaptive immune response relevant genes. ISAV isolates from different geographic regions have been shown to vary considerably in their pathogenicity for Atlantic salmon. This study aimed to characterize the Atlantic salmon TO macrophage/dendritic-like cell responses to infection with a selection of ISAV isolates of different genotypes and pathogenicity phenotypes. The first TO infection trial used ISAV isolates NBISA01 and RPC/NB-04-085-1 of high and low pathogenicity, respectively, and global gene expression analyses were carried out using approximately 16,000 gene (16K) salmonid cDNA microarrays to compare RNA samples extracted from TO cells harvested 24 and 72h post-infection versus time-matched uninfected controls. Overall, the microarray experiment showed that RPC/NB-04-085-1-infected cells had a higher total number of reproducibly dysregulated genes (88 genes: the sum of genes greater than 2-fold up- or down-regulated in all four replicate microarrays of a given comparison) than the NBISA01-infected cells (10 genes) for the combined sampling points (i.e. 24 and 72h). This microarray experiment identified several salmon genes that were differentially regulated by NBISA01 and RPC/NB-04-085-1, and which may be useful as molecular biomarkers of ISAV infection. An initial quantitative reverse transcription-polymerase chain reaction (QRT-PCR) study involving 25 microarray-identified genes confirmed the differences in the level of dysregulation of host transcripts between the two ISAV isolates (i.e. NBISA01 and RPC/NB-04-085-1). A second TO infection trial was run using a selection of four clinical ISAV isolates (Norway-810/9/99, a high pathogenicity isolate of European genotype; RPC/NB-04-085-1, a low pathogenicity isolate of European genotype; NBISA01, a high pathogenicity isolate of North American genotype; and RPC/NB-01-0593-1, an intermediate pathogenicity isolate of North American genotype), and UV-inactivated RPC/NB-04-085-1, with sampling at 24, 36, 48, 72, 96, and 120h post-infection. The microarray-identified, QRT-PCR validated suite of 24 molecular biomarkers of response to ISAV were used in a second QRT-PCR experiment to assess the TO cell gene expression responses to the four ISAV isolates at all six time points in the infection. The QRT-PCR data showed that RPC/NB-04-085-1 caused the highest fold changes of most immune-relevant genes [such as interferon-inducible protein Gig1, Mx1 protein, interferon-induced protein with tetratricopeptide repeats 5, Radical S-adenosyl methionine domain-containing protein (viperin), and several genes involved in the ISGylation pathway], followed by Norway-810/9/99. NBISA01 and RPC/NB-01-0593-01 (both of North American genotype) showed low fold up-regulation of transcripts that were highly induced by RPC/NB-04-085-1 isolate. These findings show that ISAV isolates have strain-specific variations in their ability to induce immune response genes.


Transient radiation-induced effects on solid core microstructured optical fibers.
We report transient radiation-induced effects on solid core microstructured optical fibers (MOFs). The kinetics and levels of radiation-induced attenuation (RIA) in the visible and near-infrared part of the spectrum (600 nm-2000 nm) were characterized. It is found that the two tested MOFs, fabricated by the stack-and-draw technique, present a good radiation tolerance. Both have similar geometry but one has been made with pure-silica tubes and the other one with Fluorine-doped silica tubes. We compared their pulsed X-ray radiation sensitivities to those of different classes of conventional optical fibers with pure-silica-cores or cores doped with Phosphorus or Germanium. The pulsed radiation sensitivity of MOFs seems to be mainly governed by the glass composition whereas their particular structure does not contribute significantly. Similarly for doped silica fibers, the measured spectral dependence of RIA for the MOFs cannot be correctly reproduced with the various absorption bands associated with the Si-related defects identified in the literature. However, our analysis confirms the preponderant role of self-trapped holes with their visible and infrared absorption bands in the transient behaviors of pure-silica of F-doped fibers. The results of this study showed that pure-silica or fluorine-doped MOFs, which offers specific advantages compared to conventional fibers, are promising for use in harsh environments due to their radiation tolerance.


Directed epitope delivery across the Escherichia coli outer membrane through the porin OmpF.
The porins OmpF and OmpC are trimeric β-barrel proteins with narrow channels running through each monomer that exclude molecules > 600 Da while mediating the passive diffusion of small nutrients and metabolites across the Gram-negative outer membrane (OM). Here, we elucidate the mechanism by which an entire soluble protein domain (> 6 kDa) is delivered through the lumen of such porins. Following high-affinity binding to the vitamin B(12) receptor in Escherichia coli, the bacteriocin ColE9 recruits OmpF or OmpC using an 83-residue intrinsically unstructured translocation domain (IUTD) to deliver a 16-residue TolB-binding epitope (TBE) in the center of the IUTD to the periplasm where it triggers toxin entry. We demonstrate that the IUTD houses two OmpF-binding sites, OBS1 (residues 2-18) and OBS2 (residues 54-63), which flank the TBE and bind with K(d)s of 2 and 24 μM, respectively, at pH 6.5 and 25 ºC. We show the two OBSs share the same binding site on OmpF and that the colicin must house at least one of them for antibiotic activity. Finally, we report the structure of the OmpF-OBS1 complex that shows the colicin bound within the porin lumen spanning the membrane bilayer. Our study explains how colicins exploit porins to deliver epitope signals to the bacterial periplasm and, more broadly, how the inherent flexibility and narrow cross-sectional area of an IUP domain can endow it with the ability to traverse a biological membrane via the constricted lumen of a β-barrel membrane protein.


From smoking to cancers: novel targets to neuronal nicotinic acetylcholine receptors.
Cigarette smoking bears a strong etiological association with many neovascularization-related diseases, including cancer, cardiovascular disease, and age-related macular degeneration. Cigarette smoke is a complex mixture of many compounds, including nicotine, which is the major active and addictive component of tobacco. Nicotine and its specific metabolized carcinogens directly bind to nicotinic acetylcholine receptors (nAChRs) on cell membranes and trigger the nAChR signal cascade. The nAChRs were originally thought to be ligand-gated ion channels that modulate physiological processes ranging from neurotransmission to cancer signaling. For several decades, the nAChRs served as a prototypic molecule for neurotransmitter receptors; however, they are now important therapeutic targets for various diseases, including Alzheimer's and Parkinson's diseases, schizophrenia, and even cancer. This paper describes recent advances in our understanding of the assembly, activity, and biological functions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands.


Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2.
Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive breast carcinomas, but most of these tumours become resistant to anti-oestrogen. It has been suggested that anti-oestrogen therapy may induce a HER2 signalling pathway in breast cancer cells and this may cause resistance to anti-oestrogen. Thus, it is conceivable that combined therapy with anti-oestrogen and anti-HER2 antibody might be more effective. In the present study, we investigated the effect of combined treatment with a humanized anti-HER2 monoclonal antibody, rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, on the cell growth of three human breast cancer cell lines which respectively express different levels of ER and HER2. The combined treatment enhanced the growth inhibitory effect on ML-20 cells, which express a high level of ER and a moderate level of HER2, but showed no additive effect on either KPL-4 cells, which express no ER and a moderate level of HER2, or MDA-MB-231 cells, which express no ER and a low level of HER2. It is also suggested that both the antibody and anti-oestrogen induce a G1-S blockade and apoptosis. These findings indicate that combined treatment with anti-HER2 antibody and anti-oestrogen may be useful for the treatment of patients with breast cancer expressing both ER and HER2.


Nonalcoholic fatty liver disease remission in men through regular exercise.
Recent cross-sectional and randomized controlled studies of small sample sizes revealed that regular exercise is effective for improving nonalcoholic fatty liver disease. However, there has been no large-scale longitudinal study addressing the effect of regular exercise on remission of nonalcoholic fatty liver disease. Thus, we investigated the impact of exercise on the natural history of nonalcoholic fatty liver disease. We analyzed 1,010 (860 men and 150 women) Japanese participants who received health checkups repeatedly over 10 years by a historical cohort study and were diagnosed with nonalcoholic fatty liver disease at baseline. Regular exercise was defined as participating in any kind of sports at least once a week. Nonalcoholic fatty liver disease was diagnosed by ultrasonographic images. During 10 years of follow-up, remission of nonalcoholic fatty liver disease was observed in 46.0% (396/860) of men and 48.7% (73/150) of women. In men, the adjusted hazard ratio of regular exercise for remission of nonalcoholic fatty liver disease was 1.46 (95% confidence interval 1.10-1.95, p = 0.010). However, this was not significant in women. Exercise at least once a week is implicated in the remission of nonalcoholic fatty liver disease in men.


Rectifying Attenuated Store-Operated Calcium Entry as a Therapeutic Approach for Alzheimer's Disease.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although the pathological hallmarks of AD have been identified, the derived therapies cannot effectively slow down or stop disease progression; hence, it is likely that other pathogenic mechanisms are involved in AD pathogenesis. Intracellular calcium (Ca2+) dyshomeostasis has been consistently observed in AD patients and numerous AD models and may emerge prior to the development of amyloid plaques and neurofibrillary tangles. Thus, intracellular Ca2+ disruptions are believed to play an important role in AD development and could serve as promising therapeutic intervention targets. One of the disrupted intracellular Ca2+ signaling pathways manifested in AD is attenuated storeoperated Ca2+ entry (SOCE). SOCE is an extracellular Ca2+ entry mechanism mainly triggered by intracellular Ca2+ store depletion. Maintaining normal SOCE function not only provides a means for the cell to replenish ER Ca2+ stores but also serves as a cellular signal that maintains normal neuronal functions, including excitability, neurogenesis, neurotransmission, synaptic plasticity, and gene expression. However, normal SOCE function is diminished in AD, resulting in disrupted neuronal spine stability and synaptic plasticity and the promotion of amyloidogenesis. Mounting evidence suggests that rectifying diminished SOCE in neurons may intervene with the progression of AD. In this review, the mechanisms of SOCE disruption and the associated pathogenic impacts on AD will be discussed. We will also highlight the potential therapeutic targets or approaches that may help ameliorate SOCE deficits for AD treatment.


A survey of national physicians working in an active conflict zone: the challenges of emergency medical care in Iraq.
There has been limited research on the perspectives and needs of national caregivers when confronted with large-scale societal violence. In Iraq, although the security situation has improved from its nadir in 2006-2007, intermittent bombings, and other hostilities continue. National workers remain the primary health resource for the affected populace. To assess the status and challenges of national physicians working in the Emergency Departments of an active conflict area. This study was a survey of civilian Iraqi doctors working in Emergency Departments (EDs) across Iraq, via a convenience sample of physicians taking the International Medical Corps (IMC) Doctor Course in Emergency Medicine, given in Baghdad from December 2008 through August 2009. The 148 physician respondents came from 11 provinces and over 50 hospitals in Iraq. They described cardiovascular disease, road traffic injuries, and blast and bullet injuries as the main causes of death and reasons for ED utilization. Eighty percent reported having been assaulted by a patient or their family member at least once within the last year; 38% reported they were threatened with a gun. Doctors reported seeing a median of 7.5 patients per hour, with only 19% indicating that their EDs had adequate physician staffing. Only 19% of respondents were aware of an established triage system for their hospital, and only a minority had taken courses covering ACLS- (16%) or ATLS-related (24%) material. Respondents reported a wide diversity of prior training, with only 3% having some type of specialized emergency medicine degree. The results of this study describe some of the challenges faced by national health workers providing emergency care to a violence-stricken populace. Study findings demonstrate high levels of violent behavior directed toward doctors in Iraqi Emergency Departments, as well as staffing shortages and a lack of formal training in emergency medical care.


Trends in Fetal Medicine: A 10-Year Bibliometric Analysis of Prenatal Diagnosis.
The objective is to automatically identify trends in Fetal Medicine over the past 10 years through a bibliometric analysis of articles published in Prenatal Diagnosis, using text mining techniques. We processed 2,423 full-text articles published in Prenatal Diagnosis between 2006 and 2015. We extracted salient terms, calculated their frequencies over time, and established evolution profiles for terms, from which we derived falling, stable, and rising trends. We identified 618 terms with a falling trend, 2,142 stable terms, and 839 terms with a rising trend. Terms with increasing frequencies include those related to statistics and medical study design. The most recent of these terms reflect the new opportunities of next-generation sequencing. Many terms related to cytogenetics exhibit a falling trend. A bibliometric analysis based on text mining effectively supports identification of trends over time. This scalable approach is complementary to analyses based on metadata or expert opinion.


Deaths attributed to heat, cold, and other weather events in the United States, 2006-2010.
This report examines heat-related mortality, cold-related mortality, and other weather-related mortality during 2006-2010 among subgroups of U.S. residents. Weather-related death rates for demographic and area-based subgroups were computed using death certificate information. Adjusted odds ratios for weather-related deaths among subgroups were estimated using logistic regression. During 2006-2010, about 2,000 U.S. residents died each year from weather-related causes of death. About 31% of these deaths were attributed to exposure to excessive natural heat, heat stroke, sun stroke, or all; 63% were attributed to exposure to excessive natural cold, hypothermia, or both; and the remaining 6% were attributed to floods, storms, or lightning. Weather-related death rates varied by age, race and ethnicity, sex, and characteristics of decedent's county of residence (median income, region, and urbanization level). Adjustment for region and urbanization decreased the risk of heat-related mortality among Hispanic persons and increased the risk of cold-related mortality among non-Hispanic black persons, compared with non-Hispanic white persons. Adjustment also increased the risk of heat-related mortality and attenuated the risk of cold-related mortality for counties in the lower three income quartiles. The differentials in weather-related mortality observed among demographic subgroups during 2006-2010 in the United States were consistent with those observed in previous national studies. This study demonstrated that a better understanding of subpopulations at risk from weather-related mortality can be obtained by considering area-based variables (county median household income, region, and urbanization level) when examining weather-related mortality patterns.


Discontinuing rheumatic fever prophylaxis in selected adolescents and young adults. A prospective study.
To assess the safety of discontinuing prophylaxis with antimicrobial agents in patients judged to be at relatively low risk for recurrence of acute rheumatic fever. Observational cohort study. Public health clinics in the Southeast Health District of Santiago, Chile. Fifty-nine patients (19 men, 40 women) ranging in age at study entry from 15 to 44 years (mean, 24.5 years). Forty-eight had completed their prescribed period of prophylaxis. Eleven refused or were allergic to intramuscular benzathine penicillin G and were non-compliant with oral sulfadiazine. In patients who did not have carditis during their previous attack(s), prophylaxis was discontinued after 5 years or at age 18, whichever was longer. In those with only mild mitral regurgitation or healed carditis, prophylaxis was stopped after 10 years or at age 25. Symptomatic intercurrent streptococcal throat infections were treated with antibiotics. Patients were seen every 3 months during the study (July 1982 to September 1988). For the first 4.25 years, throat cultures as well as sera samples for antistreptolysin O and anti-DNAse B assays were obtained at each visit. During laboratory surveillance, significant increases in antibody titers were detected in 56 instances (28.1 [95% CI, 21.7 to 36.5] per 100 patient-years), and 29 isolations of group A streptococci occurred (14.5 [CI, 10.1 to 20.8] per 100 patient-years). The patients were followed for a total of 3349 patient-months, during which time two acute rheumatic fever recurrences were observed (0.7 [CI, 0.2 to 2.6] per 100 patient-years). No recurrences occurred during an outbreak of acute rheumatic fever in 52 patients in the study area in 1986. These and other data indicate that acute rheumatic fever prophylaxis can safely be discontinued in young adults judged to be at low risk for recurrence and who are maintained under careful prospective surveillance.


Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition.
Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.


Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern--a recognizable polysomnographic variant with practical clinical implications.
To define the clinical and polysomnographic features of a distinct variant of obstructive sleep-disordered breathing that is remarkably mild during rapid eye movement (REM) sleep. Observational study and evaluation of polysomnographic and clinical records. American Academy of Sleep Medicine-accredited multidisciplinary sleep disorders center and laboratory. 35 medication-free subjects with clinical and polysomnographic severe obstructive sleep-disordered breathing selected for dominance of 1 of 2 disordered breathing patterns. Positive airway pressure titration. Nasal pressure was used to score respiratory events. Sleep was scored by both the standard criteria and cyclic alternating pattern (CAP), and the distribution of respiratory events was tabulated and analyzed. A distinct clinical and polysomnographic syndrome emerged, CAP-dominant sleep-disordered breathing, characterized by severe relatively short cycle obstructive events during non-REM sleep that were mild in REM sleep. Characteristics include lower body mass index, fewer apneas, and a lower hypoxic burden as reflected by frequency and severity of nocturnal oxygen saturation. During positive pressure titration, a remarkable respiratory instability emerged selectively during CAP, in contrast to stability during REM sleep. This partial treatment failure was associated with persistent clinical symptoms. This variant of sleep apnea may reflect a dominant component of respiratory instability and periodic breathing coupled with upper-airway obstruction. Its existence questions the conventional practice of calculating global respiratory indexes. Besides positive airway pressure, measures to treat periodic breathing may be required.


Model-Based Geostatistical Mapping of the Prevalence of Onchocerca volvulus in West Africa.
The initial endemicity (pre-control prevalence) of onchocerciasis has been shown to be an important determinant of the feasibility of elimination by mass ivermectin distribution. We present the first geostatistical map of microfilarial prevalence in the former Onchocerciasis Control Programme in West Africa (OCP) before commencement of antivectorial and antiparasitic interventions. Pre-control microfilarial prevalence data from 737 villages across the 11 constituent countries in the OCP epidemiological database were used as ground-truth data. These 737 data points, plus a set of statistically selected environmental covariates, were used in a Bayesian model-based geostatistical (B-MBG) approach to generate a continuous surface (at pixel resolution of 5 km x 5km) of microfilarial prevalence in West Africa prior to the commencement of the OCP. Uncertainty in model predictions was measured using a suite of validation statistics, performed on bootstrap samples of held-out validation data. The mean Pearson's correlation between observed and estimated prevalence at validation locations was 0.693; the mean prediction error (average difference between observed and estimated values) was 0.77%, and the mean absolute prediction error (average magnitude of difference between observed and estimated values) was 12.2%. Within OCP boundaries, 17.8 million people were deemed to have been at risk, 7.55 million to have been infected, and mean microfilarial prevalence to have been 45% (range: 2-90%) in 1975. This is the first map of initial onchocerciasis prevalence in West Africa using B-MBG. Important environmental predictors of infection prevalence were identified and used in a model out-performing those without spatial random effects or environmental covariates. Results may be compared with recent epidemiological mapping efforts to find areas of persisting transmission. These methods may be extended to areas where data are sparse, and may be used to help inform the feasibility of elimination with current and novel tools.


Vimentin and CP49/filensin form distinct networks in the lens which are independently modulated during lens fibre cell differentiation.
The cells of the eye lens contain the type III intermediate filament protein vimentin, as well as two other intermediate filament proteins, CP49 and filensin. These two proteins appear to be unique to the differentiated lens fibre cell. Immunoblotting and confocal microscopy were used to describe changes which occur in these three intermediate filament proteins and the networks they form during fibre cell differentiation and maturation. The vimentin network was present in both epithelial cells and some fibre cells. Fibre cells were vimentin positive up to a specific point 2-3 mm in from the lens capsule where the vimentin signal was drastically reduced. The CP49/filensin network was not present in the undifferentiated epithelial cells but emerged in the differentiating fibre cells. This latter network exhibited a principally plasma membrane localization in younger fibre cells but became more cytoplasmic in older fibre cells. This change also occurred at a distinct point in fibre cell differentiation, much earlier than the observed loss of the vimentin network. The subcellular changes in the distributions of these cytoskeletal networks were correlated to the loss of the fibre cell nucleus, another feature of fibre cell differentiation. No correlation was found to changes in the vimentin network but nuclear loss did coincide with changes in the CP49/filensin network. Concomitant with nuclear pyknosis, there were also changes in the nuclear lamina as well as infringement of the nuclear compartment by CP49, as shown by confocal microscopy. This study demonstrates vimentin and the CP49/filensin network to be independent in the lens but both networks undergo dramatic changes in subcellular distribution during the differentiation/maturation of the fibre cell. Only changes in the CP49/filensin network can be correlated to nuclear loss. Thus in the lens, unlike mammalian erythropoiesis which is also characterized by nuclear loss, the vimentin network does not appear linked to nuclear retention.


Isn't it ironic? An electrophysiological exploration of figurative language processing.
Although the neurocognitive processes underlying the comprehension of figurative language, especially metaphors and idioms, have been studied extensively, less is known about the processing of irony. In two experiments using event-related brain potentials (ERPs), we examined the types of cognitive processes involved in the comprehension of ironic and literal sentences and their relative time course. The experiments varied in modality (auditory, visual), task demands (comprehension task vs. passive reading), and probability of stimulus occurrence. ERPs consistently revealed a large late positivity (i.e., P600 component) in the absence of an N400 component for irony compared to equivalent literal sentences independent of modality. This P600 was shown to be unaffected by the factors task demands and probability of occurrence. Taken together, the findings suggest that the observed P600 is related to irony processing, and might be a reflection of pragmatic interpretation processes. During the comprehension of irony, no semantic integration difficulty arises (absence of N400), but late inferential processes appear to be necessary for understanding ironic meanings (presence of P600). This finding calls for a revision of current models of figurative language processing.


[Lymphocyte levels before treatment with subcutaneous interleukin-2 and during maintenance treatment in relation to the clinical efficacy in metastatic renal carcinoma].
the antitumor activity of IL-2 is mediated by an increase in lymphocyte number. Moreover, our previous studies have shown that therapy for 1 week/month with low-dose subcutaneous IL-2 is sufficient to maintain high levels of lymphocytes in cancer patients who have had tumor regression or stable disease (SD) in response to IL-2 immunotherapeutic cycles. This study was performed to establish whether tumor progression in cancer patients chronically treated with IL-2 may be associated with lymphocyte number decline. the study included 60 metastatic renal cell patients, who were treated with 2 induction cycles of IL-2 subcutaneous immunotherapy (6 million IU/day for 5 days/week for 6 weeks, corresponding to one cycle). Tumor regression occurred in 17/60 patients, 23 patients a SD, and the remaining 20 cases progressed. Non-progressed patients (n = 40) underwent a maintenance therapy consisting of one week of therapy every month. After a median follow-up of 18 months, 29/40 patients with response or SD had progressed. The immune investigation consisted of lymphocyte, T lymphocytes, NK cell number determination and sCD25 level detection. the mean number of lymphocytes, T lymphocytes and NK cells observed on IL-2 maintenance therapy was significantly higher than that seen before beginning the immunotherapy. Moreover, mean number of lymphocytes and mean levels of sCD25 observed at the time of tumor progression were respectively lower and higher than those seen on maintenance therapy in the same patients, without, however, significant differences. despite the importance of lymphocytes in mediating the antitumor activity of IL-2, this study shows that tumor progression in cancer patients chronically treated with low-dose IL-2 after response or SD during IL-2 induction cycles is not associated with a significant decline in lymphocyte, T lymphocyte or NK cell numbers. Further studies, carried out to analyze the functional status of immune cells at the time of tumor progression, will be necessary to define the role of immunity in cancer patients progressing under IL-2 chronic therapy.


Combining Transient Expression and Cryo-EM to Obtain High-Resolution Structures of Luteovirid Particles.
The Luteoviridae are pathogenic plant viruses responsible for significant crop losses worldwide. They infect a wide range of food crops, including cereals, legumes, cucurbits, sugar beet, sugarcane, and potato and, as such, are a major threat to global food security. Viral replication is strictly limited to the plant vasculature, and this phloem limitation, coupled with the need for aphid transmission of virus particles, has made it difficult to generate virus in the quantities needed for high-resolution structural studies. Here, we exploit recent advances in heterologous expression in plants to produce sufficient quantities of virus-like particles for structural studies. We have determined their structures to high resolution by cryoelectron microscopy, providing the molecular-level insight required to rationally interrogate luteovirid capsid formation and aphid transmission, thereby providing a platform for the development of preventive agrochemicals for this important family of plant viruses.


Tibetan medicine "RNSP" in treatment of Alzheimer disease.
Alzheimer disease (Alzheimer Disease, AD) is one of the most common type in senile dementia. Its main pathological features were that a large number of senile plaques gathered in brain extracellular and tangles fibrosis appeared in nerve cells. Currently, the pathogenesis of AD is still uncertain, and scale investigation and combined brain CT, MRI data were analyzed mainly for clinical diagnosis. Mitigation and improvement of the nervous system activity to interfere with the subsequent behavior of the patients are the main methods for treatment. In clinical no drug can really prevent and cure AD. From the view point of Tibetan medicine studies, Tibetan medicine RNSP has effect on improving memory and repairing the neurons in the brain. In this study, we combined the characteristics of AD pathology, pathogenesis, diagnosis and treatment methods to explore the feasibility of Tibetan medicine RNSP for the treatment of AD to provide new ideas for the diagnosis and treatment of AD.


Efficacy of zosteric acid sodium salt on the yeast biofilm model Candida albicans.
Candida albicans is the most notorious and the most widely studied yeast biofilm former. Design of experiments (DoE) showed that 10 mg/L zosteric acid sodium salt reduced C. albicans adhesion and the subsequent biofilm formation by at least 70%, on both hydrophilic and hydrophobic surfaces of 96-well plates. Indeed, biofilm imaging revealed the dramatic impact of zosteric acid sodium salt on biofilm thickness and morphology, due to the inability of the cells to form filamentous structures while remaining metabolically active. In the same way, 10 mg/L zosteric acid sodium salt inhibited C. albicans biofilm formation when added after the adhesion phase. Contrary to zosteric acid sodium salt, methyl zosterate did not affect yeast biofilm. In addition, zosteric acid sodium salt enhanced sensitivity to chlorhexidine, chlorine, hydrogen peroxide, and cis-2-decenoic acid, with a reduction of 0.5 to 8 log units. Preliminary in vitro studies using suitable primary cell based models revealed that zosteric acid sodium salt did not compromise the cellular activity, adhesion, proliferation or morphology of either the murine fibroblast line L929 or the human osteosarcoma line MG-63. Thus the use of zosteric acid sodium salt could provide a suitable, innovative, preventive, and integrative approach to preventing yeast biofilm formation.


[Dental surgery in patients receiving anticoagulant therapy].
It has long been a standard procedure to replace coumarin by heparin if a patient using this oral anticoagulant had to undergo dental surgery. The Quick-Value had then to exceed a certain limit before surgery could be safely performed. Today this procedure has changed in that a switch to heparin is only made for invasive and large area surgery. Simple dental extractions, small biopsies and periodontal treatments are performed under continuous oral anticoagulation and local hemostyptic measures are applied. It has been shown that the likelihood of postoperative bleeding complications after adequate local hemostasis during dental surgery is much lower than is the risk of thrombosis or embolic complication following cessation of anticoagulant medication before surgery.


Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding.
Vitamin D has anticarcinogenic properties and might influence colorectal cancer (CRC) risk, but the epidemiological evidence is inconsistent. Many mechanisms of action for vitamin D have been proposed, with some of them initiating via its binding to the vitamin D receptor (VDR). Using a large Scottish case-control study, we investigated (i) main associations between CRC, vitamin D and calcium dietary intake and 4 VDR single nucleotide polymorphisms (rs10735810, rs1544410, rs11568820, rs7975232) and (ii) interaction associations between the VDR variants, vitamin D and calcium intakes. Inverse and dose-dependent associations were found between CRC risk, dietary [Odds ratio (OR) = 0.77, 95% confidence intervals (CI) 0.63, 0.92, p-trend = 0.012] and total vitamin D (OR = 0.80, 95% CI 0.65, 0.98, p-trend = 0.014) intake in multivariable-adjusted logistic regression models, whereas neither calcium intake nor any of the VDR variants were associated with CRC. Additionally, we observed statistically significant interactions (case-control, case-only designs) between vitamin D and calcium intake and rs10735810 (p-interaction 0.02, 0.006, respectively). We conducted meta-analyses of cohort, case-control and serum studies that also showed an inverse association between dietary vitamin D intake and CRC (serum studies: combined OR = 0.70, 95% CI 0.56, 0.87). The evidence of interaction we report here further supports the inverse association between vitamin D mediated through binding to the VDR.


MAPKs and Hsc70 are critical to the protective effect of molecular hydrogen during the early phase of acute pancreatitis.
Molecular hydrogen (H2 ) has been proven to be an effective agent that can cure multiple organ diseases by reducing oxidative stress. Although the protective effect of hydrogen on acute pancreatitis (AP) has been confirmed, its molecular mechanism is still unclear. In this article, we aimed to investigate the changes in pancreatic cell protein expression associated with the protective effect of H2 against AP and attempted to uncover the molecular mechanism underlying this process. A proteomic analysis identified 73 differentially expressed proteins and generated the protein-protein interaction networks of these proteins. The results triggered our interest in mitogen-activated protein kinase (MAPK) and heat shock cognate 71 kDa protein (Hsc70). The subsequent in vitro experiments showed that H2 treatment inhibited the phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK, and activated NF-κB and the expression of tumor necrosis factor α and interleukin-1β, while simultaneously preventing the translocation of phospho-ERK, phospho-JNK, and phospho-p38 from the cytoplasm to the nucleus. Furthermore, Hsc70 expression was upregulated by H2 administration. The animal experimental results were consistent with those of the in vitro experiments. In conclusion, H2 treatment can ameliorate the inflammatory response and reduce the expression of inflammatory mediators during the early phase of AP by inhibiting the MAPK pathways and increasing Hsc70 expression.


Cytogenetic characterization and fluorescence in situ hybridization of (GATA)10 repeats on established primary cell cultures from Indian water snake (Natrix piscator) and Indian mugger (Crocodylus palustris) embryos.
Sex determination among reptiles has continued to draw the attention of geneticists and the mechanisms involved have been extensively studied and documented in the past 3 decades. The setting up of primary cell lines of reptilian tissues is an important tool in the present study which is a unique aspect not applied in earlier studies. Establishing the cell lines from various species of reptiles would help in our understanding of the mechanisms of evolution and differentiation of sex chromosomes. Therefore, in the present study, we have established for the first time primary cell cultures from Indian water snake (Natrix piscator) and Indian mugger (Crocodylus palustris) embryos. In the preliminary growth stage, 2 types of cells, fibroblast- and epithelial-like, were found to be attached and proliferating in vitro. These fibroblast-like cell cultures were later overtaken by epithelial cells. The cell lines were grown in minimal essential medium supplemented with fetal bovine serum and subcultured for a period of 8-10 months. The morphology of cell types was kept under constant observation microscopically. Interestingly, at a subsequent passage of the cells sporadically scattered neuronal-like and beating cells were observed. The suitable temperature for growth of these cell cultures was 28-30 degrees C. Chromosome analysis was performed from the actively proliferating cells, which revealed 5 pairs of macrochromosomes and 15 pairs of microchromosomes in Natrix piscator, and 15 pairs of only macrochromosomes in Crocodylus palustris. (GATA)(n) repeats are well known to be associated with sex chromosomes. Fluorescence in situ hybridization performed with (GATA)(10) repeats delineated the W chromosome in the cells of Natrix piscator which has so far not been reported. This cell culture method has presently only been applied to water snakes and crocodile embryos in the current study, but it will be employed in other reptilian species and could go a long way to being a sustainable source of primary cells. This would eventually serve as an important tool for molecular studies in reptiles and other species in the future.


Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: Results from an independent study.
Patients with myelofibrosis at intermediate-1 risk according to the International Prognostic Score System are projected to a relatively long survival; nonetheless, they may carry significant splenomegaly and/or systemic constitutional symptoms that hamper quality of life and require treatment. Since registrative COMFORT studies included only patients at intermediate-2/high International Prognostic Score System risk, safety and efficacy data in intermediate-1 patients are limited. We report on 70 intermediate-1 patients treated with ruxolitinib according to standard clinical practice that were evaluated for response using the 2013 IWG-MRT criteria. At 6 months, rates of spleen and symptoms response were 54.7% and 80% in 64 and 65 evaluable patients, respectively. At 3 months, ruxolitinib-induced grade 3 anemia and thrombocytopenia occurred in 40.6% and 2.9% of evaluable patients, respectively. Notably, 11 (15.9%) patients experienced at least one infectious event ≥grade 2. Most (82.6%) patients were still on therapy after a median follow-up of 27 months. These data support the need for standardized guidelines that may guide the decision to initiate ruxolitinib therapy in this risk category, balancing benefit expectations and potential adverse effects.


Weight gain following breast cancer diagnosis: Implication and proposed mechanisms.
Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at higher risk include women who are younger, closer to ideal body weight and who have been treated with chemotherapy. Weight gain ranges between 1 to 5 kg, and may be associated with change in body composition with gain in fat mass and loss in lean body mass. Women are unlikely to return to pre-diagnosis weight. Possible mechanisms including inactivity and metabolic changes are explored. Potential interventions are reviewed including exercise, dietary changes and pharmacologic agents. Although breast cancer prognosis does not appear to be significantly impacted, weight gain has negative consequences on quality of life and overall health. Future studies should explore change in body composition, metabolism and insulin resistance. Avoiding weight gain in breast cancer survivors following initial diagnosis and treatment should be encouraged.


Transport and variability of fecal bacteria in carbonate conglomerate aquifers.
Clastic sedimentary rocks are generally considered non-karstifiable and thus less vulnerable to pathogen contamination than karst aquifers. However, dissolution phenomena have been observed in clastic carbonate conglomerates of the Subalpine Molasse zone of the northern Alps and other regions of Europe, indicating karstification and high vulnerability, which is currently not considered for source protection zoning. Therefore, a research program was established at the Hochgrat site (Austria/Germany), as a demonstration that karst-like characteristics, flow behavior, and high vulnerability to microbial contamination are possible in this type of aquifer. The study included geomorphologic mapping, comparative multi-tracer tests with fluorescent dyes and bacteria-sized fluorescent microspheres, and analyses of fecal indicator bacteria (FIB) in spring waters during different seasons. Results demonstrate that (1) flow velocities in carbonate conglomerates are similar as in typical karst aquifers, often exceeding 100 m/h; (2) microbial contaminants are rapidly transported toward springs; and (3) the magnitude and seasonal pattern of FIB variability depends on the land use in the spring catchment and its altitude. Different groundwater protection strategies that currently applied are consequently required in regions formed by karstified carbonatic clastic rocks, taking into account their high degree of heterogeneity and vulnerability.


Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development.
Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). However, the mechanisms controlling cTEC and mTEC production from the common TEPC are not understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPCs at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development, and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue in vitro and in vivo.


Impact of AIDS Education and Training Centers on the US HIV Medical Workforce.
To examine the extent to which the AIDS Education and Training Centers (AETCs) are increasing the number and racial/ethnic diversity of HIV medical providers, in accordance with the US National HIV/AIDS Strategy (NHAS). We used administrative data from funding year 2012-2013 to describe AETC trainee characteristics, including the types of medical providers trained, compared with national estimates of available US medical providers to estimate the proportion of providers trained for every 1000 available providers by professional group and race/ethnicity. AETCs trained 56 127 unique trainees, of whom 64.1% were medical providers and 45.5% were racial/ethnic minorities. Compared to national proportions, participation in AETC training was higher among racial/ethnic minorities. The proportions of racial/ethnic minority groups trained differed across regional AETCs. AETCs support NHAS goals by expanding the HIV medical workforce and strengthening the skills of minority medical providers to deliver high quality HIV care. Public Health Implications. Some AETCs made greater contributions to training different types of racial/ethnic minorities, which indicates varied approaches are needed to best target these efforts in communities heavily impacted by HIV.


Effect on Risk of Stroke and Acute Myocardial Infarction of Nonselective Nonsteroidal Anti-Inflammatory Drugs in Patients With Rheumatoid Arthritis.
There are still debates on the association of increased cardiovascular risk with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA) because of inconsistent results. Therefore, our study aims to evaluate the transient effects of selective and nonselective NSAIDs on the risk of stroke and acute myocardial infarction (AMI) in patients with RA. We conducted a case-crossover study of 5,921 stroke or AMI patients with co-morbidity of RA. All cases were identified from the Taiwan National Health Insurance Database between January 1, 2006, and December 31, 2011, according to the International Classification of Diseases, 9th Revision and Clinical Modification diagnosis codes from inpatient claims. The index date was defined as the date of hospitalization for stroke or AMI. Exposure to NSAIDs was compared during a case period (1 to 30 days before the index date) with a control period (91 to 120 days before the index date). The adjusted odds ratios (ORs) of stroke and AMI were estimated using conditional logistic regression models. Our results showed that overall NSAIDs use increased the risk of stroke by 1.40-fold (95% confidence interval [CI] 1.25 to 1.56) and risk of AMI by 1.73-fold (95% CI 1.29 to 2.32). After classifying NSAIDs into selective and nonselective groups, only nonselective NSAIDs use significantly increased the risks of stroke (adjusted OR 1.39; 95% CI 1.25 to 1.55) and AMI (adjusted OR 1.82; 95% CI 1.37 to 2.41), respectively. In conclusion, nonselective NSAIDs were associated with an increased risk of both stroke and AMI in patients with RA.


Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D.
Secondary hyperparathyroidism is characterized by an increase in parathyroid (PT) cell number, and parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper- and hypoparathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT cell proliferation and apoptosis. PT cell proliferation has been measured by staining for proliferating cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT cell proliferation. 1,25 (OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in cell proliferation. There were no cells undergoing apoptosis in any of the experimental conditions. The secondary hyperparathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25 (OH)2D3 had no effect. These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT cell hyperplasia.


The big imitator strikes again: a case report of neurosyphilis in a patient with newly diagnosed HIV.
Neurosyphilis is the result of an infection of the central nervous system caused by the spirochete Treponema pallidum. Its clinical presentation includes meningovascular syphilis, tabes dorsalis, and dementia paralytica, resulting in a wide range of symptoms such as psychosis, Parkinsonism, and depression. A 49-year-old male was admitted to a psychiatric hospital because of social withdrawal and self-neglect, indicative of a major depression. A routine HIV-test was positive and resulted in an admission to the Antwerp University Hospital. Clinical examination showed Argyll Robertson pupils, a wide-based gait, absence of vibration sense in the lower limbs, and a MMSE-score of 25/30. Blood analysis revealed a CD4+ count of 99 cells/μL and a HIV viral load of 2,13 × 105 copies/mL plasma. A serum TPHA (T. pallidum hemagglutination assay) titre of 1/20480 and RPR (rapid plasma reagin) titre of 1/128 were detected. TPHA and RPR titre in the cerebrospinal fluid were, respectively, 1/10240 and 1/4. A brain MRI showed diffuse cortical atrophy and lesions in the white matter compatible with HIV-encephalopathy. The diagnoses of advanced HIV-infection and late neurosyphilis were made. HAART (highly active antiretroviral therapy) and high-dose IV penicillin G were started. In all patients with new-onset dementia or untreatable psychosis, neurosyphilis should always be considered. Argyll Robertson pupils are regarded as pathognomonic of neurosyphilis. The management of neurosyphilis includes high-dose IV benzyl penicillin for 10 to 14 days. Close follow-up including a lumbar puncture after 6 months is warranted to ensure treatment recovery.


MicroRNA-98 and let-7 regulate expression of suppressor of cytokine signaling 4 in biliary epithelial cells in response to Cryptosporidium parvum infection.
Expression of the cytokine-inducible Src homology 2 (CIS) protein and suppressors of cytokine signaling (SOCS) proteins represents an important element of host cell reactions in response to infection. We have demonstrated previously that Cryptosporidium parvum infection down-regulates microRNA-98 (miR-98) and let-7 to induce CIS expression in biliary epithelial cells. We report here that down-regulation of miR-98 and let-7 also coordinates epithelial expression of SOCS4 after C. parvum infection. Targeting of the SOCS4 3' untranslated region by miR-98 or let-7 resulted in translational repression. Functional manipulation of miR-98 caused reciprocal alterations in SOCS4 protein expression. Transfection of miR-98 precursor abolished C. parvum-stimulated SOCS4 up-regulation. Moreover, expression of SOCS4 in epithelial cells showed an inhibitory effect on phosphorylation of signal transducers and activators of transcription proteins induced by C. parvum. These data suggest that miRNAs play an important role in the coordinated regulation of CIS and SOCS expression in epithelial cells in response to C. parvum infection.


Streptococcus pneumoniae endohexosaminidase D, structural and mechanistic insight into substrate-assisted catalysis in family 85 glycoside hydrolases.
Endo-beta-d-glucosaminidases from family 85 of glycoside hydrolases (GH85 endohexosaminidases) act to cleave the glycosidic linkage between the two N-acetylglucosamine units that make up the chitobiose core of N-glycans. Endohexosaminidase D (Endo-D), produced by Streptococcus pneumoniae, is believed to contribute to the virulence of this organism by playing a role in the deglycosylation of IgG antibodies. Endohexosaminidases have received significant attention for this reason and, moreover, because they are powerful tools for chemoenzymatic synthesis of proteins having defined glycoforms. Here we describe mechanistic and structural studies of the catalytic domain (SpGH85) of Endo-D that provide compelling support for GH85 enzymes using a catalytic mechanism involving substrate-assisted catalysis. Furthermore, the structure of SpGH85 in complex with the mechanism-based competitive inhibitor NAG-thiazoline (K(d) = 28 microm) provides a coherent rationale for previous mutagenesis studies of Endo-D and other related GH85 enzymes. We also find GH85, GH56, and GH18 enzymes have a similar configuration of catalytic residues. Notably, GH85 enzymes have an asparagine in place of the aspartate residue found in these other families of glycosidases. We propose that this residue, as the imidic acid tautomer, acts analogously to the key catalytic aspartate of GH56 and GH18 enzymes. This topographically conserved arrangement of the asparagine residue and a conserved glutamic acid, coupled with previous kinetic studies, suggests these enzymes may use an unusual proton shuttle to coordinate effective general acid and base catalysis to aid cleavage of the glycosidic bond. These results collectively provide a blueprint that may be used to facilitate protein engineering of these enzymes to improve their function as biocatalysts for synthesizing glycoproteins having defined glycoforms and also may serve as a guide for generating inhibitors of GH85 enzymes.


Women's attitudes towards the use of complementary and alternative medicine products during pregnancy.
The aim of this study was to analyse women's attitudes towards the use of complementary and alternative medicine (CAM) products during pregnancy. The study sample was obtained via the Australian Longitudinal Study on Women's Health or ALSWH. A response rate of 79.2% (n = 1,835) was attained. Women who use herbal medicines (34.5%, n = 588) view CAM as a preventative measure, are looking for something holistic and are concerned about evidence of clinical efficacy when considering the use of these products during pregnancy. Women who use aromatherapy (17.4%, n = 319) and homoeopathy (13.3%, n = 244) want more personal control over their body and are concerned more about their own personal experience of the efficacy of CAM than clinical evidence of efficacy. As CAM use in pregnancy appears to be increasingly commonplace, insights into women's attitudes towards CAM are valuable for maternity healthcare providers.


An Examination of Parent-Reported Facilitators and Barriers to Organized Physical Activity Engagement for Youth With Neurodevelopmental Disorders, Physical, and Medical Conditions.
Organized physical activity (OPA) is an important contributor to physical, social, and emotional health and well-being; however, young people with disabilities are participating at lower rates than their peers without disabilities. This study aimed to (1) compare facilitators and barriers to OPA for young people with disabilities who currently do and do not participate in OPA and (2) to assess whether groups differed in the type of internal and external assets they reported. Parents of 218 young people (41% with a primary diagnosis of autism spectrum disorder) with a diverse representation of disabilities completed an online survey. Young people were categorized as either participants in OPA (n = 131) or non-participants (n = 87) by parent report. Non-participation was significantly predicted by the barrier "there are no activities my child enjoys" and by a lack of children's motivation and happiness during OPA. Significant internal assets differentiating participants from non-participants were the ability to understand simple instructions, love of sport, and meeting physical activity guidelines. Significant external assets were parent and sibling participation in OPA, school type, and household income. The findings from this study have important implications for the design of public health interventions that aim to promote OPA in young people with disabilities, highlighting the need to make activities enjoyable, promote participation of siblings and parents, and support low-income families to participate.


Isometamidium concentrations in the sera of cattle maintained under a chemoprophylactic regime in a tsetse-infested area of Zimbabwe.
An experiment was carried out to determine the concentrations of the trypanocidal drug isometamidium chloride in the sera of cattle maintained under a chemoprophylactic regimen at Rekomitjie, Zimbabwe, an area of high tsetse challenge in the Zimbabwe valley. In February 1993, 24 cattle at this site were treated intramuscularly with isometamidium chloride at a dose of 1.0 mg/kg body weight. Thereafter all animals were monitored regularly for 6 months for the presence of trypanosomes and sera were collected to determine the concentrations of isometamidium using an ELISA. Isometamidium treated cattle appeared to be protected against trypanosome infections for at least 18 weeks following treatment. Thereafter, three trypanosome infections were detected, between 20 and 22 weeks following treatment. In contrast, in 18 untreated control cattle at the same site, 9 trypanosome infections were detected over the first 18 weeks of the experiment. Quantification of the isometamidium concentration in sera from the drug treated cattle indicated that the apparent half-life of isometamidium in these animals was 23 days. This was similar to the half-life observed previously in cattle treated under laboratory conditions. The isometamidium ELISA was shown to be capable of quantifying drug levels in 20 out of 23 cattle for at least 70 days after treatment. There was no evidence of drug resistant trypanosomes at this site.


Changes in the ratio of tetraether to diether lipids in cattle feces in response to altered dietary ratio of grass silage and concentrates.
The distinctive membrane lipids of the archaea can contain a wide range of chemical structures. The membrane lipid composition of ruminal methanogenic archaea has not yet been characterized. In this study, we analyzed proportions of the core archaeal membrane lipids dialkyl glycerol diethers (DGDG) and glycerol dialkyl glycerol tetraether (GDGT). We analyzed the feces of beef steers consuming diets that promoted differences in ruminal conditions that were either favorable (i.e., grass silage) or challenging (i.e., concentrates) for the methanogenic archaea. There was significantly less total ether lipid in the feces of cattle consuming the concentrate diet in comparison to the grass silage diet (97 vs. 218 mg/kg DM, respectively), reflecting the inhibitory effect of dietary concentrate on methanogens. Additionally, the proportion of fecal ether lipids as GDGT was much greater in feces from cattle consuming the concentrate diet than in feces from cattle fed grass silage (90% vs. 67% GDGT). A possible explanation for this adaptation is that membrane lipids composited of GDGT lipids are less permeable to protons, thereby protecting the methanogens against low ruminal pH and helping to maintain the chemiosmotic potential (which is important for ATP production, methanogenesis, and growth). The greater proportion of fecal ether lipids as GDGT may reflect adaptation of membrane lipids within the same species, a shift toward methanogens that have a greater proportion of GDGT (e.g., Thermoplasmata), or both. The effect of ruminal environment on membrane composition means that it will be important to consider the production of both DGDG and GDGT lipids when developing a proxy for methanogenesis.


A study of physical activity comparing people with Charcot-Marie-Tooth disease to normal control subjects.
Charcot Marie Tooth disease (CMT) describes a group of hereditary neuropathies that present with distal weakness, wasting and sensory loss. Small studies indicate that people with CMT have reduced daily activity levels. This raises concerns as physical inactivity increases the risk of a range of co- morbidities, an important consideration in the long-term management of this disease. This study aimed to compare physical activity, patterns of sedentary behavior and overall energy expenditure of people with CMT and healthy matched controls. We compared 20 people with CMT and 20 matched controls in a comparison of physical activity measurement over seven days, using an activity monitor. Patterns of sedentary behavior were explored through a power law analysis. Results showed a decrease in daily steps taken in the CMT group, but somewhat paradoxically, they demonstrate shorter bouts of sedentary activity and more frequent transitions from sedentary to active behaviors. No differences were seen in energy expenditure or time spent in sedentary, moderate or vigorous activity. The discrepancy between energy expenditure and number of steps could be due to higher energy requirements for walking, but also may be due to an over-estimation of energy expenditure by the activity monitor in the presence of muscle wasting. Alternatively, this finding may indicate that people with CMT engage more in activities or movement not related to walking. Implications for Rehabilitation Charcot-Marie-Tooth disease: • People with Charcot-Marie-Tooth disease did not show a difference in energy expenditure over seven days compared to healthy controls, but this may be due to higher energy costs of walking, and/or an over estimation of energy expenditure by the activity monitor in a population where there is muscle wasting. This needs to be considered when interpreting activity monitor data in people with neuromuscular diseases. • Compared to healthy controls, people with Charcot-Marie-Tooth disease had a lower step count over seven days, but exhibited more frequent transitions from sedentary to active behaviors • High Body Mass Index and increased time spent sedentary were related factors that have implications for general health status. • Understanding the profile of physical activity and behavior can allow targeting of rehabilitation interventions to address mobility and fitness.


Dissecting the plant-insect diversity relationship in the Cape.
It has been argued that insect diversity in the Cape is disproportionately low, considering the unusually high plant diversity in this region. Recent studies have shown that this is not the case, but the precise mechanisms linking plant diversity and insect diversity in the Cape are still poorly understood. Here we use a dated genus-level phylogenetic tree of the Cape plants to assess how plant phylogenetic diversity compares with taxonomic diversity at various levels in predicting insect diversity. We find that plant phylogenetic diversity (PD) is a better predictor of insect species diversity that plant species diversity, but the number of plant genera is overall as good a predictor as PD, and much easier to calculate. The relationship is strongest between biomes, suggesting that the relationship between plant diversity and insect diversity is to a large extent indirect, both variables being driven by the same abiotic factors and possibly by common diversification, immigration and extinction histories. However, a direct relationship between plant diversity and insect diversity can be detected at fine scales, at least within certain biomes. Diversity accumulation curves also indicate that the way plant phylogenetic diversity and the number of plant genera increase over spatial scales is most similar to that for insect species; plant species show a greater increase at large spatial scales due to high numbers of local endemics.


Locking GTPases covalently in their functional states.
GTPases act as key regulators of many cellular processes by switching between active (GTP-bound) and inactive (GDP-bound) states. In many cases, understanding their mode of action has been aided by artificially stabilizing one of these states either by designing mutant proteins or by complexation with non-hydrolysable GTP analogues. Because of inherent disadvantages in these approaches, we have developed acryl-bearing GTP and GDP derivatives that can be covalently linked with strategically placed cysteines within the GTPase of interest. Binding studies with GTPase-interacting proteins and X-ray crystallography analysis demonstrate that the molecular properties of the covalent GTPase-acryl-nucleotide adducts are a faithful reflection of those of the corresponding native states and are advantageously permanently locked in a defined nucleotide (that is active or inactive) state. In a first application, in vivo experiments using covalently locked Rab5 variants provide new insights into the mechanism of correct intracellular localization of Rab proteins.


Mutations in HIV-1 reverse transcriptase cause misfolding and miscleavage by the viral protease.
Previous work on mutations in the thumb of HIV-1 reverse transcriptase (RT) showed that the majority of the mutant RTs were degraded (by the viral protease) to various extents in virions. This degradation was, in most cases, temperature sensitive, and presumably was due to a partial unfolding of the protein at 37°C. We used recombinant proteins to investigate the effects of the mutations on the thermal stability and proteolytic degradation of RT. Both subunits contribute to the stability of RT. In general, the differences in stability between the mutants and WT were greater if the mutation was in p51 rather than p66. Expressing the Pol polyprotein containing the RT mutants in Escherichia coli produced results similar to what was seen in virions; the mutant RTs were misfolded and/or degraded at 37°C, but were better folded and processed at 30°C.


Disability-Related Disparities in Access to Health Care Before (2008-2010) and After (2015-2017) the Affordable Care Act.
Objectives. To explore the effect of the Affordable Care Act (ACA) on disparities in access to health care based on disability status, as well as age, income, race, and ethnicity. Methods. In this study, I used logistic regression to analyze nationally representative data from 128 000 respondents to the US National Health Interview Survey from 2008 to 2010 and 2015 to 2017. Outcome variables were uninsurance over the previous 12 months, delayed or forgone health care for reasons of cost, and having a regular provider at a doctor's office or health clinic. Results. Over the period when the ACA was implemented, large existing disparities in access to health care were reduced for people with certain types of disabilities, young adults aged 19 to 25 years, and low-income families. Conclusions. The ACA improved overall access to health care and reduced some disparities, but substantial disparities persist. Disability status remains associated with much greater risk of delayed or forgone care, and mental health disability is associated with greater likelihood of uninsurance. Public Health Implications. The ACA partially achieved its goals and must not be weakened or rolled back. Further policy efforts are needed to address the remaining disparities.


Hypothyroidism in McCune-Albright Syndrome and Role of Bone Scan in Management of Fibrous Dysplasia: An Unusual Case Scenario with Review of Literature.
The McCune-Albright syndrome (MAS) is a triad of café-au-lait skin pigmentation, precocious puberty (PP), and polyostotic fibrous dysplasia of bone (FD). In general, FD seems to be the most common component of MAS but very rarely precocious puberty can be found in association with café-au-lait skin pigmentation in the absence of FD (about 1% of the cases). Therefore, a more clinically relevant definition of MAS is fibrous dysplasia of bone (FD) and at least one of the typical hyperfunctioning endocrinopathy and/or café-au-lait spots, with almost any combination possible. Bone scan can be the modality of choice to look for bone disease burden of fibrous dysplasia in most patients of MAS and may change the management accordingly. Most of the cases of MAS reported worldwide are associated with hyperthyroidism, up to best of our knowledge on the basis of literature search in pubmed and Google; no case was reported with hypothyroidism. Herein, we report a 12-year-old girl diagnosed with MAS and associated hypothyroidism. We have also reviewed the MAS related literature.


Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors.
The risk of atherosclerotic cardiovascular disease (ASCVD) at currently defined normal systolic blood pressure (SBP) levels in persons without ASCVD risk factors based on current definitions is not well defined. To examine the association of SBP levels with coronary artery calcium and ASCVD in persons without hypertension or other traditional ASCVD risk factors based on current definitions. A cohort of 1457 participants free of ASCVD from the Multi-Ethnic Study of Atherosclerosis who were without dyslipidemia (low-density lipoprotein cholesterol level ≥160 mg/dL or high-density lipoprotein cholesterol level <40 mg/dL), diabetes (fasting glucose level ≥126 mg/dL), treatment for hyperlipidemia or diabetes, or current tobacco use, and had an SBP level between 90 and 129 mm Hg. Participants receiving hypertension medication were excluded. Coronary artery calcium was classified as absent or present and adjusted hazard ratios (aHRs) were calculated for incident ASCVD. The study was conducted from March 27, 2018, to February 12, 2020. Systolic blood pressure. Presence or absence of coronary artery calcium and incident ASCVD events. Of the 1457 participants, 894 were women (61.4%); mean (SD) age was 58.1 (9.8) years and mean (SD) follow-up was 14.5 (3.9) years. There was an increase in traditional ASCVD risk factors, coronary artery calcium, and incident ASCVD events with increasing SBP levels. The aHR for ASCVD was 1.53 (95% CI, 1.17-1.99) for every 10-mm Hg increase in SBP levels. Compared with persons with SBP levels 90 to 99 mm Hg, the aHR for ASCVD risk was 3.00 (95% CI, 1.01-8.88) for SBP levels 100 to 109 mm Hg, 3.10 (95% CI, 1.03-9.28) for SBP levels 110 to 119 mm Hg, and 4.58 (95% CI, 1.47-14.27) for SBP levels 120 to 129 mm Hg. Beginning at an SBP level as low as 90 mm Hg, there appears to be a stepwise increase in the presence of coronary artery calcium and the risk of incident ASCVD with increasing SBP levels. These results highlight the importance of primordial prevention for SBP level increase and other traditional ASCVD risk factors, which generally seem to have similar trajectories of graded increase in risk within values traditionally considered to be normal.


Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum.
Uteroplacental acute atherosis is a pregnancy-specific lesion resembling early stages of atherosclerosis found frequently in preeclampsia. Preeclampsia is associated with an increased risk for future maternal atherosclerotic cardiovascular disease. The renin-angiotensin-system plays a role both in atherosclerosis and in preeclampsia. Circulating agonistic autoantibodies at the angiotensin-II type 1 receptor (AT1-AA) are increased in preeclampsia. We hypothesized an association between AT1-AA at delivery and postpartum with acute atherosis in pregnancy. Maternal serum and decidua basalis tissue was collected at elective cesarean section (n = 41; 24 preeclampsia, 17 normotensive controls). Circulating AT1-AA were detected by a bioassay using spontaneously beating rat cardiomyocytes at delivery (n = 41) and 5-8 years postpartum in a subgroup (n = 10). Decidual acute atherosis was assessed by immunohistochemistry. Significantly less normotensive controls (18%; 3/17) than women with preeclampsia (58%; 14/24) were AT1-AA positive at delivery, p<0.01. Uteroplacental acute atherosis and circulating AT1-AA at delivery were not significantly correlated. Postpartum, 2 prior preeclamptic women had circulating AT1-AA, both without acute atherosis in pregnancy. Our results confirm that circulating AT1-AA are present significantly more often in preeclampsia than in normotensive pregnancy, however without association to acute atherosis. Whether circulating maternal AT1-AA or acute atherosis target young women at increased long-term cardiovascular risk warrants further investigations.


Sponge bioerosion on changing reefs: ocean warming poses physiological constraints to the success of a photosymbiotic excavating sponge.
Excavating sponges are prominent bioeroders on coral reefs that in comparison to other benthic organisms may suffer less or may even benefit from warmer, more acidic and more eutrophic waters. Here, the photosymbiotic excavating sponge Cliona orientalis from the Great Barrier Reef was subjected to a prolonged simulation of both global and local environmental change: future seawater temperature, partial pressure of carbon dioxide (as for 2100 summer conditions under "business-as-usual" emissions), and diet supplementation with particulate organics. The individual and combined effects of the three factors on the bioerosion rates, metabolic oxygen and carbon flux, biomass change and survival of the sponge were monitored over the height of summer. Diet supplementation accelerated bioerosion rates. Acidification alone did not have a strong effect on total bioerosion or survival rates, yet it co-occurred with reduced heterotrophy. Warming above 30 °C (+2.7 °C above the local maximum monthly mean) caused extensive bleaching, lower bioerosion, and prevailing mortality, overriding the other factors and suggesting a strong metabolic dependence of the sponge on its resident symbionts. The growth, bioerosion capacity and likelihood of survival of C. orientalis and similar photosymbiotic excavating sponges could be substantially reduced rather than increased on end-of-the-century reefs under "business-as-usual" emission profiles.


Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.
Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.


Kinematic analysis of the thoracic limb of healthy dogs during descending stair and ramp exercises.
OBJECTIVE To compare the kinematics of the thoracic limb of healthy dogs during descent of stairs and a ramp with those during a trot across a flat surface (control). ANIMALS 8 privately owned dogs. PROCEDURES For each dog, the left thoracic limb was instrumented with 5 anatomic markers to facilitate collection of 2-D kinematic data during each of 3 exercises (descending stairs, descending a ramp, and trotting over a flat surface). The stair exercise consisted of 4 steps with a 35° slope. For the ramp exercise, a solid plank was placed over the steps to create a ramp with a 35° slope. For the flat exercise, dogs were trotted across a flat surface for 2 m. Mean peak extension, peak flexion, and range of movement (ROM) of the shoulder, elbow, and carpal joints were compared among the 3 exercises. RESULTS Mean ROM for the shoulder and elbow joints during the stair exercise were significantly greater than during the flat exercise. Mean peak extension of the elbow joint during the flat exercise was significantly greater than that during both the stair and ramp exercises. Mean peak flexion of the elbow joint during the stair exercise was significantly greater than that during the flat exercise. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that descending stairs may be beneficial for increasing the ROM of the shoulder and elbow joints of dogs. Descending stair exercises may increase elbow joint flexion, whereas flat exercises may be better for targeting elbow joint extension.


The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity.
Tissue inhibitors of metalloproteinases (TIMPs) are widely distributed in the animal kingdom and the human genome contains four paralogous genes encoding TIMPs 1 to 4. TIMPs were originally characterized as inhibitors of matrix metalloproteinases (MMPs), but their range of activities has now been found to be broader as it includes the inhibition of several of the disintegrin-metalloproteinases, ADAMs and ADAMTSs. TIMPs are therefore key regulators of the metalloproteinases that degrade the extracellular matrix and shed cell surface molecules. Structural studies of TIMP-MMP complexes have elucidated the inhibition mechanism of TIMPs and the multiple sites through which they interact with target enzymes, allowing the generation of TIMP variants that selectively inhibit different groups of metalloproteinases. Engineering such variants is complicated by the fact that TIMPs can undergo changes in molecular dynamics induced by their interactions with proteases. TIMPs also have biological activities that are independent of metalloproteinases; these include effects on cell growth and differentiation, cell migration, anti-angiogenesis, anti- and pro-apoptosis, and synaptic plasticity. Receptors responsible for some of these activities have been identified and their signaling pathways have been investigated. A series of studies using mice with specific TIMP gene deletions has illuminated the importance of these molecules in biology and pathology.


Evolutionary emergence of microRNAs in human embryonic stem cells.
Human embryonic stem (hES) cells have unique abilities to divide indefinitely without differentiating and potential to differentiate into more than 200 cell types. These properties make hES cells an ideal model system for understanding early human development and for regenerative medicine. Molecular mechanisms including cellular signaling and transcriptional regulation play important roles in hES cell differentiation. However, very little information is available on posttranscriptional regulation of hES cell pluripotency, self-renewal, and early decisions about cell fate. microRNAs (miRNAs), 22-nt long non-coding small RNAs found in plants and animals, regulate gene expression by targeting mRNAs for cleavage or translation repression. In hES cells we found that 276 miRNAs were expressed; of these, a set of 30 miRNAs had significantly changed expression during differentiation. Using a representative example, miR-302b, we show that miRNAs in human ES cells assemble into a bona fide RISC that contains Ago2 and can specifically cleave perfectly matched target RNA. Our results demonstrate that human ES cell differentiation is accompanied by changes in the expression of a unique set of miRNAs, providing a glimpse of a new molecular circuitry that may regulate early development in humans. Chromosomes 19 and X contained 98 and 40 miRNA genes, respectively, indicating that majority of miRNA genes in hES cells were expressed from these two chromosomes. Strikingly, distribution analysis of miRNA gene loci across six species including dog, rat, mouse, rhesus, chimpanzee, and human showed that miRNA genes encoded in chromosome 19 were drastically increased in chimpanzees and humans while miRNA gene loci on other chromosomes were decreased as compared with dog, rat, and mouse. Comparative genomic studies showed 99% conservation of chromosome 19 miRNA genes between chimpanzees and humans. Together, these findings reveal the evolutionary emergence, approximately 5 million years ago, of miRNAs involved in regulating early human development. One could imagine that this burst of miRNA gene clusters at specific chromosomes was part of an evolutionary event during species divergence.