Psychosocial influences on weight gain attitudes and behaviors during pregnancy.
To examine pregnant women's weight-related attitudes and behaviors in relation to a constellation of psychosocial characteristics, prepregnancy body habitus, and gestational weight gain. One hundred-thirty women with low-risk, normal pregnancies. Cross-sectional, observational study assessed attitudes about weight gain at 36 weeks' gestation. Psychosocial characteristics, including anxiety, depression, social support, emotionality, and pregnancy-specific and nonspecific stress appraisal were assessed between 28 and 36 weeks' gestation. Principal components factor analysis, Pearson correlations, t tests, and analysis of variance. A range of positive and negative attitudes about weight gain was expressed. Twenty-one percent (n=27) of the sample endorsed at least one weight-restrictive behavior during pregnancy. Women who reported more weight-restrictive behaviors were more anxious (r=.24, P<.01), depressed (r=.29,P<.001), angry (r=.29, P<.001), stressed (r=.23, P<.01), and felt less uplifted (r=-.21, P<.05) about their pregnancies in general. Higher Positive Pregnancy Body Image scores were associated with feeling better about the pregnancy in general (r=.35, P<.001), fewer depressive symptoms, and less anger (both r=.20, both P<.01). Women who were self conscious about their weight gain felt more hassled by their pregnancies (r=.21, P<.05), greater anger (r=.21, P<.05), and more support from partners (r=.22, P<.05). Prepregnancy body mass index was unrelated, but negative attitudes about weight gain existed even among women who gained within recommended ranges. Women's attitudes about weight gain in pregnancy are imbedded in their orientation toward pregnancy as well as their general psychological functioning. Effective nutrition counseling for pregnant women should include consideration of weight-restrictive behaviors, the degree to which the pregnancy is perceived as positive and uplifting, and whether weight gain attitudes may be associated with their relationship with a spouse or partner.


Curcumin inhibits Rift Valley fever virus replication in human cells.
Rift Valley fever virus (RVFV) is an arbovirus that is classified as a select agent, an emerging infectious virus, and an agricultural pathogen. Understanding RVFV-host interactions is imperative to the design of novel therapeutics. Here, we report that an infection by the MP-12 strain of RVFV induces phosphorylation of the p65 component of the NFκB cascade. We demonstrate that phosphorylation of p65 (serine 536) involves phosphorylation of IκBα and occurs through the classical NFκB cascade. A unique, low molecular weight complex of the IKK-β subunit can be observed in MP-12-infected cells, which we have labeled IKK-β2. The IKK-β2 complex retains kinase activity and phosphorylates an IκBα substrate. Inhibition of the IKK complex using inhibitors impairs viral replication, thus alluding to the requirement of an active IKK complex to the viral life cycle. Curcumin strongly down-regulates levels of extracellular infectious virus. Our data demonstrated that curcumin binds to and inhibits kinase activity of the IKK-β2 complex in infected cells. Curcumin partially exerts its inhibitory influence on RVFV replication by interfering with IKK-β2-mediated phosphorylation of the viral protein NSs and by altering the cell cycle of treated cells. Curcumin also demonstrated efficacy against ZH501, the fully virulent version of RVFV. Curcumin treatment down-regulated viral replication in the liver of infected animals. Our data point to the possibility that RVFV infection may result in the generation of novel versions of host components (such as IKK-β2) that, by virtue of altered protein interaction and function, qualify as unique therapeutic targets.


Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210.
Autophagy participates in innate immunity by eliminating intracellular pathogens. Consequently, numerous microorganisms have developed strategies to impair the autophagic machinery in phagocytes. In the current study, interactions between Leishmania major (L. m.) and the autophagic machinery of bone marrow-derived macrophages (BMDM) were analyzed. BMDM were generated from BALB/c mice, and the cells were infected with L. m. promastigotes. Transmission electron microscopy (TEM) and electron tomography were used to investigate the ultrastructure of BMDM and the intracellular parasites. Affymetrix chip analyses were conducted to identify autophagy-related messenger RNAs (mRNAs) and microRNAs (miRNAs). The protein expression levels of autophagy related 5 (ATG5), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), cathepsin E (CTSE), mechanistic target of rapamycin (MTOR), microtubule-associated proteins 1A/1B light chain 3B (LC3B), and ubiquitin (UB) were investigated through western blot analyses. BMDM were transfected with specific small interfering RNAs (siRNAs) against autophagy-related genes and with mimics or inhibitors of autophagy-associated miRNAs. The infection rates of BMDM were determined by light microscopy after a parasite-specific staining. The experiments demonstrated autophagy induction in BMDM after in vitro infection with L. m.. The results suggested a putative MTOR phosphorylation-dependent counteracting mechanism in the early infection phase and indicated that intracellular amastigotes were cleared by autophagy in BMDM in the late infection phase. Transcriptomic analyses and specific downregulation of protein expression with siRNAs suggested there is an association between the infection-specific over expression of BNIP3, as well as CTSE, and the autophagic activity of BMDM. Transfection with mimics of mmu-miR-101c and mmu-miR-129-5p, as well as with an inhibitor of mmu-miR-210-5p, demonstrated direct effects of the respective miRNAs on parasite clearance in L. m.-infected BMDM. Furthermore, Affymetrix chip analyses revealed a complex autophagy-related RNA network consisting of differentially expressed mRNAs and miRNAs in BMDM, which indicates high glycolytic and inflammatory activity in the host macrophages. Autophagy in L. m.-infected host macrophages is a highly regulated cellular process at both the RNA level and the protein level. Autophagy has the potential to clear parasites from the host. The results obtained from experiments with murine host macrophages could be translated in the future to develop innovative and therapeutic antileishmanial strategies for human patients.


Dental care behaviour in Switzerland
Improvements in oral health are changing the requirements for oral health care provision. This study assessed the frequency and major reason of dental visits and personal oral hygiene measures in Switzerland, and temporal trends in visit frequency. The number of dental visits in the previous twelve months, the reason for these visits, and the prevalence of oral hygiene measures were quantified from weighted data from the 2012 Swiss Health Survey. The frequency of dental visits in 2012 was compared with previous surveys (1992–2007). Almost two thirds of subjects reported visiting a dentist and almost half had visited a dental hygienist in the previous twelve months. Voluntary (33%) or recall check-ups (25%) were the most common reasons for the last dental visit across age groups. Treatment needs including caries/filling/endodontic treatment (10%), crowns/FDP/RDP/implants (8%), toothache (5%), extraction (5%), periodontal complaints (2%), or orthodontic appliances (2%) were more heterogeneously distributed across age groups. One in ten subjects had dental implants; prevalence increased with increasing age as did the number of missing teeth. Use of interdental cleaning devices and frequent tooth brushing were more common among subjects with few or no missing teeth and among subjects with higher versus lower income or education. Oral health awareness varied with a higher awareness in women than in men and in subjects with higher versus lower income or education. The prevalence of dental implants and dental hygienist's visits has increased in Switzerland since 2002, but oral hygiene measures remained stable.


Consequences of sex education on teen and young adult sexual behaviors and outcomes.
This study examined whether formal sex education is associated with sexual health behaviors and outcomes using recent nationally representative survey data. Data used were from 4,691 male and female individuals aged 15-24 years from the 2006-2008 National Survey of Family Growth. Weighted bivariate and multivariate analyses were conducted by gender, estimating the associations of sex education by type (only abstinence, abstinence and birth control, or neither) before first sexual intercourse, and sexual behaviors and outcomes. Receipt of sex education, regardless of type, was associated with delays in first sex for both genders, as compared with receiving no sex education. Respondents receiving instruction about abstinence and birth control were significantly more likely at first sex to use any contraception (odds ratio [OR] = 1.73, females; OR = 1.91, males) or a condom (OR = 1.69, females; OR = 1.90, males), and less likely to have an age-discrepant partner (OR = .67, females; OR = .48, males). Receipt of only abstinence education was not statistically distinguishable in most models from receipt of either both or neither topics. Among female subjects, condom use at first sex was significantly more likely among those receiving instruction in both topics as compared with only abstinence education. The associations between sex education and all longer-term outcomes were mediated by older age at first sex. Sex education about abstinence and birth control was associated with healthier sexual behaviors and outcomes as compared with no instruction. The protective influence of sex education is not limited to if or when to have sex, but extends to issues of contraception, partner selection, and reproductive health outcomes.


Association Between Hemoglobin A1c and Surgical Morbidity in Elective Foot and Ankle Surgery.
The current guidelines for the management of diabetes in adults have recommended strict glycemic control, with a target hemoglobin A1c of 7.0%. Increasing evidence has shown that strict glycemic control decreases the risk of developing the organ system complications associated with diabetes. Elevated hemoglobin A1c levels have been theorized as a risk factor for complications after elective foot and ankle surgery. To test this hypothesis, we reviewed the Department of Veterans Affairs national administrative and clinical databases for a 6-year period (January 2008 to December 2013). During this period, 21,854 diabetic patients had a recorded hemoglobin A1c measurement within 1 year before undergoing elective foot and ankle surgery. We then identified those patients who had experienced postoperative complications within 30 days of elective foot or ankle surgery using the International Classification of Diseases, ninth revision, codes. The complications were classified into 4 groups: infection, wound healing, mechanical failure, and cardiovascular/pulmonary. The overall 30-day postoperative complication rate was 3.2%. The most common complication was infection (42.3%), followed by mechanical failure (33.4%), cardiovascular/pulmonary (18.4%), and wound healing (5.8%). The average hemoglobin A1c of a patient who had experienced a complication was 6.29% compared with 6.11% for a patient who had not experienced 1 of the 4 complications (p < .001). Logistic regression analysis revealed that for each 1% increase in hemoglobin A1c, the odds of developing a complication increased by 5%. More significant was the 1.78 times increased risk of developing a complication for patients with neuropathy (95% confidence interval 1.45 to 2.20; p = .0001). Even more notable was the associated risk of complications after elective foot and ankle surgery for those patients with comorbid conditions. Patients demonstrated 3.08 times the risk of developing a complication when the patient had 2 to 3 identified comorbid conditions associated with diabetes mellitus (95% confidence interval 2.42 to 3.92; p = .0001). The present retrospective observational investigation has demonstrated glycemic control influences the postoperative complication rates in elective foot and ankle surgery. However, the data collected from the present study have also demonstrated that the complication rates are multifactorial. Comorbid conditions and the presence of peripheral neuropathy also play a significant role in determining a patient's risk of complications after elective foot and ankle surgery.


Privatization in health and human services: a critique.
Privatization currently enjoys wide appeal as a solution to public problems. Supporters of privatization hope that shifting responsibility for the funding, administration, and delivery of services to private organizations and individuals will spur market competition and thus lower costs, improve service effectiveness, and enhance program quality. An increasingly common form of privatization in health and human services is contracting with nonprofit organizations. Such contracting, in practice, does not follow market principles but is, instead, fraught with politics and inadequate information and built on long-term relationships between government and contract agencies. The operations and practices of contracting have important implications for the ongoing debate on the desirability of vouchers for health care insurance and for reform in the contracting process.


Representation in the human brain of food texture and oral fat.
Important factors that influence food palatability are its texture and fat content. We investigated their representation in the human brain using event-related functional magnetic resonance imaging. It was shown that the viscosity of oral stimuli is represented in the (primary) taste cortex in the anterior insula, in which activation was proportional to the log of the viscosity of a cellulose stimulus (carboxymethyl cellulose), and was also produced by sucrose. Oral viscosity was also represented in a mid-insular region that was posterior to the taste cortex. Third, it was found that oral delivery of fatty vegetable oil activates both of these insular cortex regions, the hypothalamus, and the dorsal midanterior cingulate cortex. Fourth, it was found that the ventral anterior cingulate cortex, where it borders the medial orbitofrontal cortex, was activated by oral fat independently of its viscosity and was also activated by sucrose taste. This ventral anterior cingulate region thus represents two indicators of the energy content and palatability of foods. These are the first investigations of the oral sensory representation of food texture and fat in the human brain, and they start to reveal brain mechanisms that may be important in texture-related sensory properties of foods that make them palatable and that may accordingly play a role in the hedonic responses to foods, the control of food intake, and obesity.


The tail end of the moth: clarifying species boundaries.
The search by naturalists for good characters upon which to base both classifications and determinations of species led some 19th century entomologists to put their faith in insect genitalia as a criteria by which they could differentiate between and classify forms. Karl Jordan was such an entomologist, who turned to these tiny structures as an aid to his work as a museum curator to identify, describe and classify moths and butterflies. In his writings on the subject he also demonstrated how the attempts of systematists to order the diversity of nature had profound implications for the efforts of biologists to explain the origin of that diversity. However, Jordan's plan of how to do systematics well required much more than convincing biologists of the importance of museum work. It also depended on refining the priorities of a natural history community that worked according to diverse means, priorities and methods during a tumultuous century.


The cross-national epidemiology of specific phobia in the World Mental Health Surveys.
Although specific phobia is highly prevalent, associated with impairment, and an important risk factor for the development of other mental disorders, cross-national epidemiological data are scarce, especially from low- and middle-income countries. This paper presents epidemiological data from 22 low-, lower-middle-, upper-middle- and high-income countries. Data came from 25 representative population-based surveys conducted in 22 countries (2001-2011) as part of the World Health Organization World Mental Health Surveys initiative (n = 124 902). The presence of specific phobia as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition was evaluated using the World Health Organization Composite International Diagnostic Interview. The cross-national lifetime and 12-month prevalence rates of specific phobia were, respectively, 7.4% and 5.5%, being higher in females (9.8 and 7.7%) than in males (4.9% and 3.3%) and higher in high- and higher-middle-income countries than in low-/lower-middle-income countries. The median age of onset was young (8 years). Of the 12-month patients, 18.7% reported severe role impairment (13.3-21.9% across income groups) and 23.1% reported any treatment (9.6-30.1% across income groups). Lifetime co-morbidity was observed in 60.5% of those with lifetime specific phobia, with the onset of specific phobia preceding the other disorder in most cases (72.6%). Interestingly, rates of impairment, treatment use and co-morbidity increased with the number of fear subtypes. Specific phobia is common and associated with impairment in a considerable percentage of cases. Importantly, specific phobia often precedes the onset of other mental disorders, making it a possible early-life indicator of psychopathology vulnerability.


Benefits and risks of furosemide in acute kidney injury.
Furosemide, a potent loop diuretic, is frequently used in different stages of acute kidney injury, but its clinical roles remain uncertain. This review summarises the pharmacology of furosemide, its potential uses and side effects, and the evidence of its efficacy. Furosemide is actively secreted by the proximal tubules into the urine before reaching its site of action at the ascending limb of loop of Henle. It is the urinary concentrations of furosemide that determine its diuretic effect. The severity of acute kidney injury has a significant effect on the diuretic response to furosemide; a good 'urinary response' may be considered as a 'proxy' for having some residual renal function. The current evidence does not suggest that furosemide can reduce mortality in patients with acute kidney injury. In patients with acute lung injury without haemodynamic instability, furosemide may be useful in achieving fluid balance to facilitate mechanical ventilation according to the lung-protective ventilation strategy.


Normal body temperature and the effects of age, sex, ambient temperature and body mass index on normal oral temperature: a prospective, comparative study.
Body temperature is an indicator of health status. However, thermoregulatory function is thought to decline with aging. To determine normal body temperature and the effects of age, sex, ambient temperature (AT), and body mass index (BMI) on normal oral temperatures (OTs). A prospective four group comparative descriptive design was used to compare four cohorts: young adults in summer, older adults in summer, young adults in winter, and older adults in winter. The OT of 519 community dwelling older adults ages 65-95 and 540 younger adults ages 20-64 was compared. The OT was taken with an electronic thermometer between 8 a.m. and 10 a.m. during summer and winter in 2007 in Taipei, Taiwan. There was no difference in mean OT between the <65 and > or =65 groups measured during winter. However, the mean OT of the <65 group was 0.11 degrees C lower than the > or =65 group measured in the summer. Subjects (> or =85 years) had a higher correlation coefficient (r=0.48) between OT and AT than those in the 65-74 year older group (r=0.31) and 75-84 year older group (r=0.23). Moreover this study found that the mean OT of older females was higher than that of older males in both winter and summer cohorts. Finally, multiple regression analysis results indicated AT and sex were predictors of OT while age and BMI were not a significant predictor of OT. These four factors together accounted for 9.4% of the variance in the overall sample (age 20-95), 12.8%, in those 65-95 and 28.2% for those, > or =85 years old. These findings help to clarify discrepancies in the literature. The OT of those over age 65 and those 20-64 was lower than the accepted 37 degrees C norm. However, "older is colder" does not apply to all older adults. Our findings indicate AT and sex rather than age alone account for temperature variation in older adults with normal baseline temperature. Further investigation is needed to identify potential risk factors of impaired thermoregulation in older adults.


Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature.
Vascular development requires an orderly exchange of signals between growing vessels and their supporting tissues, but little is known of the intracellular signaling pathways underlying this communication. We find that mice with disruptions of both NFATc4 and the related NFATc3 genes die around E11 with generalized defects in vessel assembly as well as excessive and disorganized growth of vessels into the neural tube and somites. Since calcineurin is thought to control nuclear localization of NFATc proteins, we introduced a mutation into the calcineurin B gene that prevents phosphatase activation by Ca(2+) signals. These CnB mutant mice exhibit vascular developmental abnormalities similar to the NFATc3/c4 null mice. We show that calcineurin function is transiently required between E7.5 and E8.5. Hence, early calcineurin/NFAT signaling initiates the later cross-talk between vessels and surrounding tissues that pattern the vasculature.


Stem cell treatment for chronic lung diseases.
Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn.


The effect of a fibre supplement compared to a healthy diet on body composition, lipids, glucose, insulin and other metabolic syndrome risk factors in overweight and obese individuals.
Optimum levels and types of dietary fibre that provide the greatest beneficial effects on metabolic syndrome risk factors in overweight and obese individuals have yet to be determined in clinical trials. The present parallel design study compared the effects of fibre intake from a healthy diet v. a fibre supplement (psyllium) or a healthy diet plus fibre supplement on fasting lipids, glucose, insulin and body composition. Overweight/obese adults were randomised to either control (with placebo), fibre supplement (FIB), healthy eating plus placebo (HLT) or healthy eating plus fibre supplement (HLT-FIB). There was a significant increase in fibre intake in HLT-FIB, HLT and FIB groups up to 59, 31 and 55 g, respectively, at 12 weeks when compared to control (20 g). Weight, BMI and % total body fat were significantly reduced in FIB and HLT-FIB groups, with weight and BMI significantly reduced in the HLT group compared with control at 12 weeks. HLT-FIB and HLT groups had significant reductions in TAG and insulin compared with control at 6 and 12 weeks, and in insulin compared with the FIB group at 12 weeks. The HLT-FIB, HLT and FIB groups all had significant reductions in total cholesterol and LDL-cholesterol compared with control after 6 and 12 weeks. The present study demonstrated that simply adding psyllium fibre supplementation to a normal diet was sufficient to obtain beneficial effects in risk factors. However, a high-fibre diet consisting of a psyllium supplement plus fibre from a healthy diet provided the greatest improvements in metabolic syndrome risk factors.


Structural study of the Fox-1 RRM protein hydration reveals a role for key water molecules in RRM-RNA recognition.
The Fox-1 RNA recognition motif (RRM) domain is an important member of the RRM protein family. We report a 1.8 Å X-ray structure of the free Fox-1 containing six distinct monomers. We use this and the nuclear magnetic resonance (NMR) structure of the Fox-1 protein/RNA complex for molecular dynamics (MD) analyses of the structured hydration. The individual monomers of the X-ray structure show diverse hydration patterns, however, MD excellently reproduces the most occupied hydration sites. Simulations of the protein/RNA complex show hydration consistent with the isolated protein complemented by hydration sites specific to the protein/RNA interface. MD predicts intricate hydration sites with water-binding times extending up to hundreds of nanoseconds. We characterize two of them using NMR spectroscopy, RNA binding with switchSENSE and free-energy calculations of mutant proteins. Both hydration sites are experimentally confirmed and their abolishment reduces the binding free-energy. A quantitative agreement between theory and experiment is achieved for the S155A substitution but not for the S122A mutant. The S155 hydration site is evolutionarily conserved within the RRM domains. In conclusion, MD is an effective tool for predicting and interpreting the hydration patterns of protein/RNA complexes. Hydration is not easily detectable in NMR experiments but can affect stability of protein/RNA complexes.


Extraskeletal osteosarcoma of the thorax in a goat: case report.
This report describes the results of clinical, ultrasonographic and computed tomographic examination of a 16-year-old goat with extraskeletal osteosarcoma of the thorax. The lead clinical signs were abnormal condition and demeanour, fever, tachycardia, tachypnoea, dyspnoea and dilated jugular veins. Ultrasonographic examination of the thorax revealed a precardial mass, measuring 16.4 by 11.4 by 14.2 cm. Computed tomographic examination showed dorsocaudal displacement of the trachea, heart and lungs to the right. A tentative diagnosis of mediastinal or pleural neoplasia was made, and the goat was euthanased and necropsied. A definitive diagnosis was based on histological examination of the mass. To our knowledge, this case report is the first description of extraskeletal osteosarcoma of the thorax in goats and serves to broaden the diagnostic spectrum of thoracic diseases in this species. Extraskeletal osteosarcoma should be part of the differential diagnosis in goats with thoracic tumours.


Worldwide timing of growth faltering: revisiting implications for interventions.
Our goal was to describe worldwide growth-faltering patterns by using the new World Health Organization (WHO) standards. We analyzed information available from the WHO Global Database on Child Growth and Malnutrition, comprising data from national anthropometric surveys from 54 countries. Anthropometric data comprise weight-for-age, length/height-for-age, and weight-for-length/height z scores. The WHO regions were used to aggregate countries: Europe and Central Asia; Latin America and the Caribbean; North Africa and Middle East; South Asia; and sub-Saharan Africa. Sample sizes ranged from 1000 to 47 000 children. Weight for length/height starts slightly above the standard in children aged 1 to 2 months and falters slightly until 9 months of age, picking up after that age and remaining close to the standard thereafter. Weight for age starts close to the standard and falters moderately until reaching approximately -1 z at 24 months and remaining reasonably stable after that. Length/height for age also starts close to the standard and falters dramatically until 24 months, showing noticeable bumps just after 24, 36, and 48 months but otherwise increasing slightly after 24 months. Comparison of child growth patterns in 54 countries with WHO standards shows that growth faltering in early childhood is even more pronounced than suggested by previous analyses based on the National Center for Health Statistics reference. These findings confirm the need to scale up interventions during the window of opportunity defined by pregnancy and the first 2 years of life, including prevention of low birth weight and appropriate infant feeding practices.


New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism.
Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Genetic characterization of a large cohort of Brazilian CHH patients. A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.


[Perception of mistreatment during medical residency training].
Because previous investigations show that mistreatment during residency is frequent we undertook this research to assess the prevalence of psychological abuse, physical violence and sexual harassment in residency training programs and the professional status of perpetrators. Through a literature review and a previous qualitative study we developed a self-administered questionnaire. Thirteen events that could be experienced by residents and ten possible perpetrators were described in the questionnaire. Residents were asked to record whether they had experienced these events, at least once, and who was responsible. This survey was distribuided among the residents from three hospitals of Buenos Aires city. A total of 322 residents answered the questionnaire (55% women) 72% of whom worked in clinical programs, 22% in surgical programs, and 6% in diagnostic programs. Mistreatment was reported by 89% of the residents. On average each resident recorded 8 different episodes of mistreatment, such as being criticized for not completing administrative work (75%), being shouted at (64%), being humiliated in public (57%), sexual harassment (10%), being exposed to pornographic material without permission (7%), being hit or pushed (15%), suffering racial or religious discrimination (10%). The most common perpetrators were senior residents (26%), chief resident (19%), attending physicians (14%), and nurses (8%). Mistreatment and abuse are commonly experienced by residents in training programs. A multidisciplinary approach is needed to address this problem in the training environment.


Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Ketamine is an N-methyl-D-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine. Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg · h; mean dose 1.1 mg · kg · h) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway. Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = -0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065). These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.


Relationship between work context and adherence to a clinical practice guideline for peripheral venous catheters among registered nurses in pediatric care.
It is known that registered nurses' (RNs') work context is related to their use of research and that it can affect nurse and patient satisfaction, as well as the outcomes of care. However, little is known about the relationship between work context and nurses' adherence to clinical practice guidelines. The aim of this study was to describe RNs' adherence to a clinical practice guideline (CPG) on the management of peripheral venous catheters (PVCs), their perceptions of work context, and how nurses' work context and characteristics relate to guideline adherence. This cross-sectional survey was conducted at a large pediatric university hospital in Sweden. Data were collected through a questionnaire on RNs' adherence to components of a CPG and by using the Alberta Context Tool to assess the nurses' perceptions of work context, including leadership, culture, feedback processes, and other organizational characteristics. Work context--in the form of structural and electronic resources, information sharing activities, and feedback processes--was in different ways associated with the adherence to the CPG components. The RNs' adherence on unit level varied: half the units demonstrated complete adherence on disinfection of hands, whereas a majority of the units reported less than 70% adherence on the use of disposable gloves and the daily inspection of a PVC site. Our findings indicate that components in one CPG might require diverse implementation strategies because they are linked to different contextual factors.


Storage of carbon dioxide in offshore sediments.
The battle to reduce greenhouse gas emissions and prevent the most dangerous consequences of climate change will be waged across multiple fronts, including efforts to increase energy efficiency; efforts to deploy nonfossil fuel sources, including renewable and nuclear energy; and investment in adaptation to reduce the impacts of the climate change that will occur regardless of the actions we take. But with more than 80% of the world's energy coming from fossil fuel, winning the battle also requires capturing CO2 from large stationary sources and storing that CO2 in geologic repositories. Offshore geological repositories have received relatively little attention as potential CO2 storage sites, despite their having a number of important advantages over onshore sites, and should be considered more closely.


Targeted disruption of the mouse topoisomerase I gene by camptothecin selection.
Topoisomerase I has ubiquitous roles in important cellular functions such as replication, transcription, and recombination. In order to further characterize this enzyme in vivo, we have used gene targeting to inactivate the mouse Top-1 gene. A selection protocol using the topoisomerase I inhibitor camptothecin facilitated isolation of embryonic stem cell clones containing an inactivated allele; isolation of correctly targeted clones was enhanced 75-fold over that achieved by normal selection procedures. The disrupted Top-1 allele is embryonic lethal when homozygous, and development of such embryos fails between the 4- and 16-cell stages. Both sperm and oocytes containing the inactive allele maintain viability through the fertilization point, and thus gene expression of topoisomerase I is not required for gamete viability. These studies demonstrate that topoisomerase I is essential for cell growth and division in vivo. The Top-1 gene was also shown to be linked to the agouti locus.


Successful Clozapine Re-Challenge After Suspected Clozapine-Induced Myocarditis.
BACKGROUND Clozapine plays a unique role in the management of treatment-resistant schizophrenia (TRS). Clozapine re-challenge following an episode of myocarditis is controversial, with a very limited literature, although it may be crucial in the recovery of certain patients. To date and to the best of our knowledge, only 10 of 22 studied cases reported successful clozapine retrial after myocarditis. CASE REPORT We present the case of a 22-year-old Hispanic man with treatment-resistant schizophrenia and polysubstance use disorder (methamphetamine, cannabis, and alcohol) initiated on aggressive clozapine titration after lack of response to several other therapies. Approximately 16 days after clozapine trial, the patient developed cardiac function impairment, presenting with chest pain, notable elevation in several biomarkers (troponin: 0.72 ng/ml, ESR >100 mm/h, CRP: 20.8 mg/dl, and BNP: 999 ng/ml), and a depressed ejection fraction at 25%. Further assessments also showed positive hepatitis A serology. Following discontinuation of clozapine and providing supportive care, the patient's physical symptoms resolved. He had a relapse of psychotic symptoms, which were refractory to treatment with other antipsychotic agents. Subsequently, the patient underwent a second clozapine trial under close monitoring, with resolution of his psychosis. Repeated echocardiography demonstrated improved EF to 50%, transaminitis was resolved, repeat blood test results were normalized, and the patient was discharged while he was stabilized and asymptomatic. CONCLUSIONS This case adds to the previous case reports and suggests that clinicians may consider clozapine re-challenge following an episode of myocarditis based on clinical judgment, on a case-by-case basis, and under close monitoring. We highlight the need for development of clinical guidelines for clozapine re-challenge.


Mast cells and inflammatory heart disease: potential drug targets.
Inflammation underlies the pathogenesis of many common cardiovascular diseases (CVD) such as myocardial infarction, atherosclerosis, myocarditis and dilated cardiomyopathy. Allergic disorders like allergic rhinitis and asthma, both chronic inflammatory conditions, have recently been linked to increased CVD and death. Studies have found that increased IgE levels, eosinophilia, positive skin-prick tests, self-reported asthma and enzymes that regulate leukotriene synthesis (5-lipoxygenase) predict a high risk for atherosclerosis, stroke and myocardial infarction. Mast cells (MCs), cells involved in the pathogenesis of allergy and asthma, are emerging as key players in the regulation of inflammation and fibrosis in the heart and vasculature. Our laboratory has found that MC numbers are increased in mice susceptible to developing chronic dilated cardiomyopathy. The fibrosis associated with chronic heart disease is increased by MC degranulation. MCs can also act as antigen-presenting cells increasing inflammation in the heart through Toll-like receptor-4 signaling and increased proinflammatory cytokine production. Similar inflammatory mechanisms are observed for myocarditis and atherosclerosis. Many of the drugs currently used to reduce heart disease act on mediators/ pathways downstream of MC degranulation. An improved understanding of the role of MCs in regulating inflammation and fibrosis will enable researchers and clinicians to better treat heart disease.


Gallic Acid Inhibits Proliferation and Induces Apoptosis in Lymphoblastic Leukemia Cell Line (C121).
Leukemia is known as the world's fifth most prevalent cancer. New cytotoxic drugs have created considerable progress in the treatment, but side effects are still the important cause of mortality. Plant derivatives have been recently considered as important sources for the treatment of various diseases, including cancer. Gallic acid (GA) is a polyhydroxyphenolic compound with a wide range of biological functions. The aim of the present study was to evaluate the effect of GA on proliferation inhibition and apoptosis induction of a lymphoblastic leukemia cell line. Jurkat cell (C121) line was cultured in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (FBS) with different concentrations of GA (10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 μM) for 24, 48 and 72 hours. The effect of GA on cell viability was measured using MTS assay. Induction of apoptosis was evaluated with Annexin V-FITC/PI kit and flow cytometry. Data were analyzed by SPSS version 20 using Kruskal-Wallis and Dunn's multiple comparison tests. Decline of cell viability to less than 50% was observed at 60.3±1.6, 50.9±1.5, and 30.9±2.8 μM concentration after 24, 48, and 72 hours incubation, respectively. All concentrations of GA (10, 30, 50 and 80 μM) enhanced apoptosis compared to the control (P<0.05). The results demonstrate that the polyphenolic compound, GA, is effective in inhibition of proliferation and induction of apoptosis in Jurkat cell line. It is recommended to study the mechanism of apoptosis induction in future investigations.


Ganoderma lucidum polysaccharide loaded sodium alginate micro-particles prepared via electrospraying in controlled deposition environments.
Ganoderma lucidum polysaccharide (GLP) is a functional food source deployed in preventative medicine. However, applications utilizing GLP are limited due to oxidative and acidic environmental damage. Advances in preserving GLP structure (and therefore function), in situ, will diversify their applications within biomedical fields (drug and antibacterial active delivery via the enteral route). In this study, GLP loaded sodium alginate (NaAlg) micro-particles (size range 225-355μm) were generated using the electrospray (ES) process. The loading capacity and encapsulation efficiency of GLP for composite particles (collected at different temperatures) were ∼23% and 71%, respectively. The collection substrate (CaCl2, 1-20w/v%) concentration was explored and preliminary findings indicated a 10w/v% solution to be optimal. The process was further modified by manipulating the collection environment temperature (∼25 to 50°C). Based on this, NaAlg/GLP micro-particles were engineered with variable surface morphologies (porous and crinkled), without effecting the chemical composition of either material (GLP and NaAlg). In-vitro release studies demonstrated pH responsive release rates. Modest release of GLP from micro-particles in simulated gastric fluid (pH ∼1.7) was observed, while rapid release was exhibited under simulated intestinal conditions (pH ∼7.4). Release of GLP from NaAlg beads was the greatest from samples prepared at elevated environmental temperatures. These findings demonstrate a facile route to fabricate GLP-NaAlg loaded micro-particles with various shapes, surface topographies and release characteristics via a one-step ES process.


Bacterial microcompartment-directed polyphosphate kinase promotes stable polyphosphate accumulation in E. coli.
Processes for the biological removal of phosphate from wastewater rely on temporary manipulation of bacterial polyphosphate levels by phased environmental stimuli. In E. coli polyphosphate levels are controlled via the polyphosphate-synthesizing enzyme polyphosphate kinase (PPK1) and exopolyphosphatases (PPX and GPPA), and are temporarily enhanced by PPK1 overexpression and reduced by PPX overexpression. We hypothesised that partitioning PPK1 from cytoplasmic exopolyphosphatases would increase and stabilise E. coli polyphosphate levels. Partitioning was achieved by co-expression of E. coli PPK1 fused with a microcompartment-targeting sequence and an artificial operon of Citrobacter freundii bacterial microcompartment genes. Encapsulation of targeted PPK1 resulted in persistent phosphate uptake and stably increased cellular polyphosphate levels throughout cell growth and into the stationary phase, while PPK1 overexpression alone produced temporary polyphosphate increase and phosphate uptake. Targeted PPK1 increased polyphosphate in microcompartments 8-fold compared with non-targeted PPK1. Co-expression of PPX polyphosphatase with targeted PPK1 had little effect on elevated cellular polyphosphate levels because microcompartments retained polyphosphate. Co-expression of PPX with non-targeted PPK1 reduced cellular polyphosphate levels. Thus, subcellular compartmentalisation of a polymerising enzyme sequesters metabolic products from competing catabolism by preventing catabolic enzyme access. Specific application of this process to polyphosphate is of potential application for biological phosphate removal.


Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel.
Sodium channels are inhibited by a chemically diverse group of compounds. In the last decade entirely new structural classes with superior properties have been discovered, and novel therapeutic uses of sodium channel inhibitors (SCIs) have been suggested. Many promising novel drug candidates have been described and characterized. Published structure-activity relationship studies, pharmacophore models, and mutagenesis studies seem to lag behind, dealing with only a limited group of inhibitor compounds. The abundance of novel compounds requires an organized comparison of drug potencies. The affinity of sodium channel inhibitors can vary typically ten- to thousand-fold depending on the voltage protocol; therefore comparison of electrophysiology data is difficult. In this study we describe a method for standardization of these data with the help of a simple model of state-dependence. We derived hyperpolarized (resting) and depolarized (generally termed "inactivated") state affinities for the studied drugs, which made the measurements comparable. We show a rank order of SCIs based on resting and inactivated affinity values. In an attempt to define basic chemical requirements for sodium channel inhibitor activity we investigated the dependence of both resting and inactivated state affinities on individual chemical descriptors. Lipophilicity (most often expressed by the logP value) is the single most important determinant of SCI potency. We investigated the independent impact of several other calculated chemical properties by standardizing drug potencies for logP values. By combining these two approaches: standardization of affinity values, and standardization of potencies, we concluded that while resting affinity is mostly determined by lipophilicity, inactivated state affinity is determined by a more complex interaction of chemical properties, including hydrogen bond acceptors, aromatic rings, and molecular weight.


Co-analgesic therapy for arthroscopic supraspinatus tendon repair pain using a dietary supplement containing Boswellia serrata and Curcuma longa: a prospective randomized placebo-controlled study.
The cuff tendon that is most prone to full-thickness rotator cuff tears is the supraspinatus (SSP). Arthroscopic SSP repair ensures good to satisfactory mid- to long-term clinical outcomes. However, the intense postoperative pain reduces rehabilitation compliance and is cause of patient dissatisfaction. Many natural compounds act by inhibiting inflammatory pathways in a similar way to anti-inflammatory drugs This was a prospective randomized trial designed to assess the analgesic effect of a dietary supplement (DS) containing Boswellia serrata and Curcuma longa in a population of subjects with full-thickness SSP tendon tear treated by arthroscopy. Three weeks before surgery, patients were randomized to receive Tendisulfur(®) (group T) or a placebo (group P) for 2 months. The primary outcome measure was subjective VAS pain. Secondary outcomes measures were Constant-Murley score simple shoulder test, and patient global assessment (PGA) scores. Patients were assessed immediately at baseline and subsequently at 1, 2, 4, 6, 8, 12, and 24 weeks. Stratification of pain scores and subscores demonstrated significantly lower overall pain scores in group T versus group P at 1 week (p = 0.0477), and lower but not significantly different scores on week 2 (p = 0.0988); at subsequent time points, differences were not significant (p > 0.05). PGA scores were good in all subjects. In conclusion, this study provides objective data on the effect of a DS containing natural substances, added to standard analgesics, on postoperative RC pain. DS alleviated short and partially mid-term pain, while long-term pain was unchanged. This limitation can probably be addressed by a dosage increase over the first 4 weeks and by extending treatment by 1 or 2 months.


Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins.
Chronic inflammatory disorders, such as rheumatoid arthritis, are often accompanied by systemic bone loss, which is thought to occur through inflammatory cytokine-mediated stimulation of osteoclast resorption and inhibition of osteoblast function. However, the mechanisms involved in osteoblast inhibition remain poorly understood. Here we test the hypothesis that increased Smad ubiquitin regulatory factor 1 (Smurf1)-mediated degradation of the bone morphogenetic protein pathway signaling proteins mediates reduced bone formation in inflammatory disorders. Osteoblasts derived from bone marrow or long bone samples of adult tumor necrosis factor (TNF) transgenic (TNF-Tg) mice were used in this study. TNF decreased the steady-state levels of Smad1 and Runx2 protein similarly to those in long bones of TNF-Tg mice. In the presence of the proteasome inhibitor MG132, TNF increased accumulation of ubiquitinated Smad1 protein. TNF administration over calvarial bones caused decreases in Smad1 and Runx2 protein levels and mRNA expression of osteoblast marker genes in wild-type, but not in Smurf1(-/-) mice. Vertebral bone volume and strength of TNF-Tg/Smurf1(-/-) mice were examined by a combination of micro-CT, bone histomorphometry, and biomechanical testing and compared with those from TNF-Tg littermates. TNF-Tg mice had significantly decreased bone volume and biomechanical properties, which were partially rescued in TNF-Tg/Smurf1(-/-) mice. We conclude that in chronic inflammatory disorders where TNF is increased, TNF induces the expression of ubiquitin ligase Smurf1 and promotes ubiquitination and proteasomal degradation of Smad1 and Runx2, leading to systemic bone loss. Inhibition of ubiquitin-mediated Smad1 and Runx2 degradation in osteoblasts could help to treat inflammation-induced osteoporosis.


Resistance exercise enhances myofibrillar protein synthesis with graded intakes of whey protein in older men.
Feeding stimulates robust increases in muscle protein synthesis (MPS); however, ageing may alter the anabolic response to protein ingestion and the subsequent aminoacidaemia. With this as background, we aimed to determine in the present study the dose-response of MPS with the ingestion of isolated whey protein, with and without prior resistance exercise, in the elderly. For the purpose of this study, thirty-seven elderly men (age 71 (sd 4) years) completed a bout of unilateral leg-based resistance exercise before ingesting 0, 10, 20 or 40 g of whey protein isolate (W0-W40, respectively). Infusion of l-[1-13C]leucine and l-[ring-13C6]phenylalanine with bilateral vastus lateralis muscle biopsies were used to ascertain whole-body leucine oxidation and 4 h post-protein consumption of MPS in the fed-state of non-exercised and exercised leg muscles. It was determined that whole-body leucine oxidation increased in a stepwise, dose-dependent manner. MPS increased above basal, fasting values by approximately 65 and 90 % for W20 and W40, respectively (P < 0·05), but not with lower doses of whey. While resistance exercise was generally effective at stimulating MPS, W20 and W40 ingestion post-exercise increased MPS above W0 and W10 exercised values (P < 0·05) and W40 was greater than W20 (P < 0·05). Based on the study, the following conclusions were drawn. At rest, the optimal whey protein dose for non-frail older adults to consume, to increase myofibrillar MPS above fasting rates, was 20 g. Resistance exercise increases MPS in the elderly at all protein doses, but to a greater extent with 40 g of whey ingestion. These data suggest that, in contrast to younger adults, in whom post-exercise rates of MPS are saturated with 20 g of protein, exercised muscles of older adults respond to higher protein doses.


Is sodium current present in human sinoatrial node cells?
Pacemaker activity of the sinoatrial node has been studied extensively in various animal species, but is virtually unexplored in man. As such, it is unknown whether the fast sodium current (I(Na)) plays a role in the pacemaker activity of the human sinoatrial node. Recently, we had the unique opportunity to perform patch-clamp experiments on single pacemaker cells isolated from a human sinoatrial node. In 2 out of the 3 cells measured, we observed large inward currents with characteristics of I(Na). Although we were unable to analyze the current in detail, our findings provide strong evidence that I(Na) is present in human sinoatrial node pacemaker cells, and that this I(Na) is functionally available at potentials negative to -60 mV.


Contributions of cardiac "funny" (f) channels and sarcoplasmic reticulum Ca2+ in regulating beating rate of mouse and guinea pig sinoatrial node.
The aim of this study was to investigate the effects on spontaneous beating rate of mouse atrial preparations following selective block of cardiac "funny" (f) channels, I(f), and/or suppression of sarcoplasmic reticulum (SR) function in the absence and presence of β-adrenoceptor stimulation. ZD7288 [to block I(f)] caused a substantial reduction (222 ± 13 bpm) in beating rate from 431 ± 14 to 209 ± 14 bpm, ryanodine alone (to block SR Ca(2+) release) reduced beating rate by 105 ± 11 bpm, with subsequent addition of ZD7288 further reducing rate by 57 ± 9 bpm. Cyclopiazonic acid (CPA) alone (to inhibit Ca(2+) reuptake by the SR) reduced beating rate by 148 ± 13 bpm with subsequent addition of ZD7288 further reducing rate by 79 ± 12 bpm. In additional experiments measuring Ca(2+) transients in the SA node region using Rhod-2, effects of ivabradine and ZD7288 on rate were again substantially reduced after CPA. Effects of CPA alone on rate developed much more slowly than effects on Ca(2+) transient amplitude. ZD7288, ivabradine, and CPA reduced the slope and maximum response of the log(concentration)-response curves for effects of isoprenaline on beating rate. Very little response to isoprenaline remained after treatment with CPA followed by ZD7288. Similar changes in isoprenaline log(concentration)-response curves were seen in guinea pig preparations. These observations are consistent with a role for Ca(2+) released from the SR in regulating I(f) and therefore beating rate of SA node preparations; there appear to be additional contributions of SR-derived Ca(2+) to effects of β-adrenoceptor stimulation on beating rate that are independent of I(f).


Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes.
Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes. Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C ≤ 9%. The patients had a liquid meal test at the 1-, 6-, and 12-month visits, which included measurement of C-peptide, proinsulin, GLP-1, glucagon, and insulin antibodies (IA). Patients in remission at 6 and 12 months had significantly higher levels of proinsulin compared to non-remitting patients (p < 0.0001, p = 0.0002). An inverse association between proinsulin and IDAA1C was found at 1 and 6 months (p = 0.0008, p = 0.0022). Proinsulin was positively associated with C-peptide (p < 0.0001) and IA (p = 0.0024, p = 0.0068, p < 0.0001) at 1, 6, and 12 months. Glucagon (p < 0.0001 and p < 0.02) as well as GLP-1 (p = 0.0001 and p = 0.002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002). In type 1 diabetes, patients in partial remission have higher levels of proinsulin together with lower levels of GLP-1 and glucagon compared to patients not in remission. In new onset type 1 diabetes proinsulin level may be a sign of better residual beta-cell function.


The project for objective measures using computational psychiatry technology (PROMPT): Rationale, design, and methodology.
Depressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. New technology allows quantification of features that clinicians perceive as reflective of disorder severity, such as facial expressions, phonic/speech information, body motion, daily activity, and sleep. Major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders as well as healthy controls are recruited for the study. A psychiatrist/psychologist conducts conversational 10-min interviews with participants ≤10 times within up to five years of follow-up. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms. The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity. UMIN000021396, University Hospital Medical Information Network (UMIN).


Spin-transfer torque generated by a topological insulator.
Magnetic devices are a leading contender for the implementation of memory and logic technologies that are non-volatile, that can scale to high density and high speed, and that do not wear out. However, widespread application of magnetic memory and logic devices will require the development of efficient mechanisms for reorienting their magnetization using the least possible current and power. There has been considerable recent progress in this effort; in particular, it has been discovered that spin-orbit interactions in heavy-metal/ferromagnet bilayers can produce strong current-driven torques on the magnetic layer, via the spin Hall effect in the heavy metal or the Rashba-Edelstein effect in the ferromagnet. In the search for materials to provide even more efficient spin-orbit-induced torques, some proposals have suggested topological insulators, which possess a surface state in which the effects of spin-orbit coupling are maximal in the sense that an electron's spin orientation is fixed relative to its propagation direction. Here we report experiments showing that charge current flowing in-plane in a thin film of the topological insulator bismuth selenide (Bi2Se3) at room temperature can indeed exert a strong spin-transfer torque on an adjacent ferromagnetic permalloy (Ni81Fe19) thin film, with a direction consistent with that expected from the topological surface state. We find that the strength of the torque per unit charge current density in Bi2Se3 is greater than for any source of spin-transfer torque measured so far, even for non-ideal topological insulator films in which the surface states coexist with bulk conduction. Our data suggest that topological insulators could enable very efficient electrical manipulation of magnetic materials at room temperature, for memory and logic applications.


Aboriginal and Queer Identity/ies in Western Australia: When There is a Need to Know in Therapeutic Settings.
A central question for the exploratory Aboriginal and LGBTQ+ researcher led project 'Breaking the Silence: Being Indigenous and identifying LGBTQ+' (Breaking the Silence) is how provision of genuinely inclusive service responses for Aboriginal and Torres Strait Islander people identifying as LGBTQ+ can be developed. This article presents the qualitative findings of this mixed-methods research project to show how organizational staff working in health, education and social support services in Western Australia consider the Aboriginal LGBTQ+ identity/experience. Analysis of the written, interview and focus group responses to a question about the relevance of LGBTQ+ identity show that these questions need to be considered and evaluated within diverse service cultures and philosophies of services. Staff views are diverse and organizational consensus on the relevance (or not) of LGBTQ+ identity needs to be the precursor before the development or consideration of changes to service delivery and models.


Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms.
Bariatric surgery is the most effective treatment for severe obesity, producing marked sustained weight loss with associated reduced morbidity and mortality. Roux-en-Y gastric bypass surgery (RYGBP), the most commonly performed procedure, was initially viewed as a hybrid restrictive-malabsorptive procedure. However, over the last decade, it has become apparent that alternative physiologic mechanisms underlie its beneficial effects. RYGBP-induced altered feeding behavior, including reduced appetite and changes in taste/food preferences, is now recognized as a key driver of the sustained postoperative weight loss. The brain ultimately determines feeding behavior, and here we review the mechanisms by which RYGBP may affect central appetite-regulating pathways.


Access to antiretroviral therapy in HIV-infected children aged 0-19 years in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium, 2004-2015: A prospective cohort study.
Access to antiretroviral therapy (ART) is a global priority. However, the attrition across the continuum of care for HIV-infected children between their HIV diagnosis and ART initiation is not well known. We analyzed the time from enrollment into HIV care to ART initiation in HIV-infected children within the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium. We included 135,479 HIV-1-infected children, aged 0-19 years and ART-naïve at enrollment, between 1 January 2004 and 31 December 2015, in IeDEA cohorts from Central Africa (3 countries; n = 4,948), East Africa (3 countries; n = 22,827), West Africa (7 countries; n = 7,372), Southern Africa (6 countries; n = 93,799), Asia-Pacific (6 countries; n = 4,045), and Latin America (7 countries; n = 2,488). Follow-up in these cohorts is typically every 3-6 months. We described time to ART initiation and missed opportunities (death or loss to follow-up [LTFU]: last clinical visit >6 months) since baseline (the date of HIV diagnosis or, if unavailable, date of enrollment). Cumulative incidence functions (CIFs) for and determinants of ART initiation were computed, with death and LTFU as competing risks. Among the 135,479 children included, 99,404 (73.4%) initiated ART, 1.9% died, 1.4% were transferred out, and 20.4% were lost to follow-up before ART initiation. The 24-month CIF for ART initiation was 68.2% (95% CI: 67.9%-68.4%); it was lower in sub-Saharan Africa-ranging from 49.8% (95% CI: 48.4%-51.2%) in Central Africa to 72.5% (95% CI: 71.5%-73.5%) in West Africa-compared to Latin America (71.0%, 95% CI: 69.1%-72.7%) and the Asia-Pacific (78.3%, 95% CI: 76.9%-79.6%). Adolescents aged 15-19 years and infants <1 year had the lowest cumulative incidence of ART initiation compared to other ages: 62.2% (95% CI: 61.6%-62.8%) and 66.4% (95% CI: 65.7%-67.0%), respectively. Overall, 49.1% were ART-eligible per local guidelines at baseline, of whom 80.6% initiated ART. The following children had lower cumulative incidence of ART initiation: female children (p < 0.01); those aged <1 year, 2-4 years, 5-9 years, and 15-19 years (versus those aged 10-14 years, p < 0.01); those who became eligible during follow-up (versus eligible at enrollment, p < 0.01); and those receiving care in low-income or lower-middle-income countries (p < 0.01). The main limitations of our study include left truncation and survivor bias, caused by deaths of children prior to enrollment, and use of enrollment date as a proxy for missing data on date of HIV diagnosis, which could have led to underestimation of the time between HIV diagnosis and ART initiation. In this study, 68% of HIV-infected children initiated ART by 24 months. However, there was a substantial risk of LTFU before ART initiation, which may also represent undocumented mortality. In 2015, many obstacles to ART initiation remained, with substantial inequities. More effective and targeted interventions to improve access are needed to reach the target of treating 90% of HIV-infected children with ART.


Nucleotide-Induced Conformational Changes in Escherichia coli DnaA Protein Are Required for Bacterial ORC to Pre-RC Conversion at the Chromosomal Origin.
DnaA oligomerizes when bound to origins of chromosomal replication. Structural analysis of a truncated form of DnaA from Aquifex aeolicus has provided insight into crucial conformational differences within the AAA+ domain that are specific to the ATP- versus ADP- bound form of DnaA. In this study molecular docking of ATP and ADP onto Escherichia coli DnaA, modeled on the crystal structure of Aquifex aeolicus DnaA, reveals changes in the orientation of amino acid residues within or near the vicinity of the nucleotide-binding pocket. Upon limited proteolysis with trypsin or chymotrypsin ADP-DnaA, but not ATP-DnaA generated relatively stable proteolytic fragments of various sizes. Examined sites of limited protease susceptibility that differ between ATP-DnaA and ADP-DnaA largely reside in the amino terminal half of DnaA. The concentration of adenine nucleotide needed to induce conformational changes, as detected by these protease susceptibilities of DnaA, coincides with the conversion of an inactive bacterial origin recognition complex (bORC) to a replication efficient pre-replication complex (pre-RC) at the E. coli chromosomal origin of replication (oriC).


The differential risk factors of physically forced and alcohol- or other drug-enabled sexual assault among university women.
The Campus Sexual Assault Study examined whether undergraduate women's victimization experiences prior to college and lifestyle activities during college were differentially associated with the type of sexual assault they experienced: physically forced sexual assault and incapacitated sexual assault. Self-reported data collected using a Web-based survey administered to more than 5,000 undergraduate women at two large public universities indicated that victimization experiences before college were differentially associated with the risk of experiencing these two types of sexual assault during college. Women who experienced forced sexual assault before college were at very high risk of experiencing forced sexual assault during college (odds ratio [OR] = 6.6). Women who experienced incapacitated sexual assault before college were also at very high risk of experiencing incapacitated sexual assault during college (OR = 3.7). Moreover, women's substance use behaviors during college, including getting drunk and using marijuana, were strongly associated with experiencing incapacitated sexual assault but were not associated with experiencing forced sexual assault. Implications for education and prevention programs, as well as future research directions, are discussed.


Intrauterine growth pattern and birthweight discordance in twin pregnancies: a retrospective study.
Twins, compared to singletons, have an increased risk of perinatal mortality and morbidity, due mainly to a higher prevalence of preterm birth and low birthweight. Intrauterine growth restriction (IUGR) is also common and can affect one or both fetuses. In some cases, however, one twin is much smaller than the other (growth discordance). Usually, high birthweight discordance is associated with increased perinatal morbidity. The aim of this study is to describe the epidemiological features of a population of twins at birth, with particular reference to the interpretation and clinical effects of birthweight discordance. We evaluated retrospectively the clinical features of 70 infants born from twin pregnancies and assessed birthweight discordance in 31 pregnancies where both twins were followed at our institution. Discordance was treated both as a continuous and a categorical variable, using a cutoff of 18%. Possible relationships between birthweight discordance and other variables, such as maternal age, gestational age, birthweight percentile, number of SGA newborns in the pair, Hematocrit (Ht) discordance and neonatal anemia, prevalence of malformations, neonatal morbidity and death, were analyzed. In our cohort birthweight percentile decreased slightly with increasing gestational age. Birthweight discordance, on the contrary, increased slightly with the increase of gestational age.A high discordance is associated to the presence of one SGA twin, with the other AGA or LGA. In our population, all 6 pregnancies in which discordance exceeded 18% belonged to this category (one SGA twin).Ht discordance at birth is associated to the presence of neonatal anemia in a twin, but it is not significantly related to weight discordance.Finally, in our case history, weight discordance is not associated in any way with the prevalence of malformations, morbidity and mortality. Birthweight discordance is an important indicator of complications that act asymmetrically on the two fetuses, affecting intrauterine growth in one of them, and usually determining the birth of a SGA infant.Our case history shows a significant statistical association between pair discordance and IUGR in one of the twins, but we could not demonstrate any relationship between discordance and the prevalence of malformations, morbidity and mortality.


Model for laser Doppler measurements of blood flow in tissue.
A theory is developed which relates quasi-elastic light scattering measurements to blood flow in tissue micro-vasculature. We assume that the tissue matrix surrounding the blood cells is a strong diffuser of light and that moving erythrocytes, therefore, are illuminated by a spatially distributed source. Because the surrounding tissue is considered to be stationary, Doppler shifts in the frequency of the scattered light arise only from photon interactions with the moving blood cells. The theory implies that the time decay of the photon autocorrelation function scales proportionally with cell size and inversely with mean translational speed. Analysis of multiple interactions of photons with moving cells indicates the manner in which spectral measurements additionally are sensitive to changes in blood volume. Predictions are verified by measurements of particle flow in model tissues.


Unzipping and shearing DNA with electrophoresed nanoparticles in hydrogels.
We show electric control of unzipping and shearing dehybridization of a DNA duplex anchored to a hydrogel. Tensile force is applied by electrophoresing (25 V cm-1) gold nanoparticles pulling the DNA duplex. The pulled DNA strand is gradually released from the hydrogel. The unzipping release rate is faster than shearing; for example, 3-fold for a 15 base pair duplex, which helps to design electrically driven DNA devices.


Perceived state of self during motion can differentially modulate numerical magnitude allocation.
Although a direct relationship between numerical allocation and spatial attention has been proposed, recent research suggests that these processes are not directly coupled. In keeping with this, spatial attention shifts induced either via visual or vestibular motion can modulate numerical allocation in some circumstances but not in others. In addition to shifting spatial attention, visual or vestibular motion paradigms also (i) elicit compensatory eye movements which themselves can influence numerical processing and (ii) alter the perceptual state of 'self', inducing changes in bodily self-consciousness impacting upon cognitive mechanisms. Thus, the precise mechanism by which motion modulates numerical allocation remains unknown. We sought to investigate the influence that different perceptual experiences of motion have upon numerical magnitude allocation while controlling for both eye movements and task-related effects. We first used optokinetic visual motion stimulation (OKS) to elicit the perceptual experience of either 'visual world' or 'self'-motion during which eye movements were identical. In a second experiment, we used a vestibular protocol examining the effects of perceived and subliminal angular rotations in darkness, which also provoked identical eye movements. We observed that during the perceptual experience of 'visual world' motion, rightward OKS-biased judgments towards smaller numbers, whereas leftward OKS-biased judgments towards larger numbers. During the perceptual experience of 'self-motion', judgments were biased towards larger numbers irrespective of the OKS direction. Contrastingly, vestibular motion perception was found not to modulate numerical magnitude allocation, nor was there any differential modulation when comparing 'perceived' vs. 'subliminal' rotations. We provide a novel demonstration that numerical magnitude allocation can be differentially modulated by the perceptual state of self during visual but not vestibular mediated motion.


Blood and Cerebrospinal Fluid α-Tocopherol and Selenium Concentrations in Neonatal Foals with Neuroaxonal Dystrophy.
Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α-tocopherol (α-TP)-deficient diet. Intramuscular α-TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α-TP in healthy foals. Serum and CSF α-TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life. Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α-TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals. Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed. Significant decreases in blood, CSF α-TP and Se found in the first year of life in all foals, with most significant changes in serum α-TP from 4-150 days. Dam α-TP and Se significantly influenced blood concentrations in foals. Injection of α-TP and Se did not significantly increase CSF Se, blood or CSF α-TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF α-TP through 120 days. Injection of α-TP and Se at 4 days of age does not significantly increase blood or CSF α-TP. Despite all 14 foals remaining deficient in α-TP, only the 4 genetically predisposed foals developed NAD/EDM.


Insights into the low-temperature adaptation and nutritional flexibility of a soil-persistent Escherichia coli.
An understanding of the survival capacity of Escherichia coli in soil is critical for the evaluation of its role as a faecal indicator. Recent reports that E. coli can become long-term residents in maritime temperate soils have raised the question of how the organism survives and competes for niche space in the suboptimal soil environment. The ability of an environmental isolate to utilize 380 substrates was assessed together with that of a reference laboratory strain (E. coli K12) at both 15 and 37 °C. At 15 °C, the environmental strain could utilize 161 substrates, with only 67 utilizable by the reference strain, while at 37 °C, 239 and 223 substrates could be utilized by each strain respectively. An investigation into the cold response of the strains revealed that E. coli K12 was found to reduce the expression of biosynthetic proteins at 15 °C, while the environmental isolate seemed to switch on proteins involved in stress response, suggesting low-temperature adaptation in the latter. Taken together, the results indicate that the environmentally persistent E. coli strain is well adapted to use a wide range of nutrient sources at 15 °C and to direct its protein expression to maintain a relatively fast growth rate at low temperature.


Hyperpolarized 13C pyruvate mouse brain metabolism with absorptive-mode EPSI at 1T.
The expected signal in echo-planar spectroscopic imaging experiments was explicitly modeled jointly in spatial and spectral dimensions. Using this as a basis, absorptive-mode type detection can be achieved by appropriate choice of spectral delays and post-processing techniques. We discuss the effects of gradient imperfections and demonstrate the implementation of this sequence at low field (1.05T), with application to hyperpolarized [1-13C] pyruvate imaging of the mouse brain. The sequence achieves sufficient signal-to-noise to monitor the conversion of hyperpolarized [1-13C] pyruvate to lactate in the mouse brain. Hyperpolarized pyruvate imaging of mouse brain metabolism using an absorptive-mode EPSI sequence can be applied to more sophisticated murine disease and treatment models. The simple modifications presented in this work, which permit absorptive-mode detection, are directly translatable to human clinical imaging and generate improved absorptive-mode spectra without the need for refocusing pulses.


Renal involvement in autoimmune connective tissue diseases.
Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that.In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA.In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions.


Nutritional Status and Changes in Body Weight in Patients with Multiple System Atrophy.
The importance of nutritional management in neurodegenerative diseases is increasingly recognized in the clinical setting. However, few reports have examined the nutritional intake in patients with multiple system atrophy (MSA). Here, we investigated changes in daily caloric intake, body mass index (BMI) and nutritional status during the disease course of MSA. We performed a single-hospital study of 82 consecutive patients with probable MSA according to the consensus criteria. We determined daily caloric intake, the level of activities of daily living (ADL; independent, wheelchair-bound or bedridden) and BMI at the time of admission. Nutritional status was also evaluated using biochemical nutritional markers including serum albumin, total cholesterol and lymphocyte count. Although daily caloric intake decreased with ADL level deterioration (p < 0.01), no significant differences were observed in BMI among ADL levels. Serum albumin also decreased with ADL deterioration (p < 0.01); however, no significant differences were observed for serum total cholesterol or lymphocyte count with respect to ADL level. We demonstrated that patients with advanced stage MSA may develop malnutrition in the absence of a decrease in BMI. Moreover, serum albumin level may be useful for evaluating nutritional changes in MSA patients.


Expansion of bovine chondrocytes on microcarriers enhances redifferentiation.
Functional cartilage implants for orthopedic surgery or in vitro tissue evaluation can be created from expanded chondrocytes and biodegradable scaffolds. Expansion of chondrocytes in two-dimensional culture systems results in their dedifferentiation. The hallmark of this process is the switch of collagen synthesis from type II to type I. The aim of this study was to evaluate the postexpansion chondrogenic potential of microcarrier-expanded bovine articular chondrocytes in pellet cultures. A selection of microcarriers was screened for initial attachment of chondrocytes. On the basis of those results and additional selection criteria related to clinical application, Cytodex-1 microcarriers were selected for further investigation. Comparable doubling times were obtained in T-flask and microcarrier cultures. During propagation on Cytodex-1 microcarriers, cells acquired a spherical-like morphology and the presence of collagen type II was detected. Both observations are indicative of a differentiated chondrocyte. Pellet cultures of microcarrier-expanded cells showed cartilage-like morphology and staining for proteoglycans and collagen type II after 14 days. In contrast, pellets of T-flask-expanded cells had a fibrous appearance and showed abundant staining only for collagen type I. Therefore, culture of chondrocytes on microcarriers may offer useful and cost-effective cell expansion opportunities in the field of cartilage tissue engineering.


In vitro comparison of complementary interactions between synthetic linear/branched oligo/poly-L-lysines and tissue plasminogen activator by means of high-performance monolithic-disk affinity chromatography.
The recently discovered serine protease called tissue plasminogen activator (t-PA) enables efficient dissolution of blood clots. t-PA works by converting plasminogen into its active form, plasmin, dissolving the major component of blood clots, fibrin. The activation of plasminogen by t-PA is enhanced by the presence of fibrin, and this is probably due to the fact that both plasminogen and t-PA possess high affinity binding sites for fibrin. Besides fibrin, fibrin monomers and some fibrin(ogen) degradation products, certain synthetic polymers (for instance, poly-L-lysines) can provide the same stimulation of plasminogen activation. The recently developed high-performance monolithic-disk chromatography, HPMDC, could become the most convenient way to study biological pairs of interest. The inherent speed of HPMDC isolation facilitates the recovery of a biologically active product, since the exposure to putative denaturing influences, such as solvents or temperature, is reduced. The better mass transfer mechanism (convection rather than diffusion) allows to consider only the biospecific reaction as time limiting. The step-by-step modeling of hypothetical affinity pairs between t-PA and different types of oligo/polymer forms of linear and branched lysine derivatives obtained both by initiated polycondensation and solid-phase peptide synthesis using HPMDC seemed to be possible and a quite useful tool. The results of quantitative evaluation of such affinity interactions were compared with those established for natural affinity counterparts to t-PA (monoclonal antibodies, plasminogen, fibrinogen). The role of steric structure of lysine ligands was observed and analyzed. The results allowing to make the practical choice of affinity systems will be used for development of fast and efficient analytical and preparative methods for the downstream processes of recombinant production of this valuable enzyme.


Flavonoid-rich fruit and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease--FLAVURS: a randomized controlled trial.
Observed associations between increased fruit and vegetable (F&V) consumption, particularly those F&Vs that are rich in flavonoids, and vascular health improvements require confirmation in adequately powered randomized controlled trials. This study was designed to measure the dose-response relation between high-flavonoid (HF), low-flavonoid (LF), and habitual F&V intakes and vascular function and other cardiovascular disease (CVD) risk indicators. A single-blind, dose-dependent, parallel randomized controlled dietary intervention study was conducted. Male and female low-F&V consumers who had a ≥ 1.5-fold increased risk of CVD (n = 174) were randomly assigned to receive an HF F&V, an LF F&V, or a habitual diet, with HF and LF F&V amounts sequentially increasing by 2, 4, and 6 (+2, +4, and +6) portions/d every 6 wk over habitual intakes. Microvascular reactivity (laser Doppler imaging with iontophoresis), arterial stiffness [pulse wave velocity, pulse wave analysis (PWA)], 24-h ambulatory blood pressure, and biomarkers of nitric oxide (NO), vascular function, and inflammation were determined at baseline and at 6, 12, and 18 wk. In men, the HF F&V diet increased endothelium-dependent microvascular reactivity (P = 0.017) with +2 portions/d (at 6 wk) and reduced C-reactive protein (P = 0.001), E-selectin (P = 0.0005), and vascular cell adhesion molecule (P = 0.0468) with +4 portions/d (at 12 wk). HF F&Vs increased plasma NO (P = 0.0243) with +4 portions/d (at 12 wk) in the group as a whole. An increase in F&Vs, regardless of flavonoid content in the groups as a whole, mitigated increases in vascular stiffness measured by PWA (P = 0.0065) and reductions in NO (P = 0.0299) in the control group. These data support recommendations to increase F&V intake to ≥ 6 portions daily, with additional benefit from F&Vs that are rich in flavonoids, particularly in men with an increased risk of CVD.


Determination of toxic heavy metals in sea water by FAAS after preconcentration with a novel chelating resin.
A solid phase extraction procedure was developed for preconcentration of toxic heavy metals such as cadmium, cobalt, copper, manganese, lead and zinc in sea water samples. A microcolumn packed with 6-[(4-hydroxyphenyl)diazenyl]naphthalene-2,3-diol-formaldehyde (HPDN-F) resin acts as a sorbent to retain the analyte ions by forming metal chelates. The retained trace level metal was subsequently eluted with 1 mol/L HCl and the acid eluent was analysed by Flame Atomic Absorption Spectrophotometer (FAAS). The HPDN-F chelating resin and its metal chelates were characterized by spectral and thermal analysis. The chelating property of the HPDN-F resin towards divalent metal ions was studied as a function of pH and preconcentration flow rate. The recoveries of cadmium, cobalt, copper, manganese, lead and zinc under the optimum working conditions were above 95%. The relative standard deviations were < 2%. The limits of detection were < 0.1 microg/L. The method presented was applied for the determination of cadmium, cobalt, copper, manganese, lead and zinc in sea water samples.


General Practitioners' experiences of bereavement care and their educational support needs: a qualitative study.
General Practitioners (GPs) are well-positioned to provide grief support to patients. Most GPs view the provision of bereavement care as an important aspect of their role and the GP is the health professional that many people turn to when they need support. We aimed to explore GPs' understandings of bereavement care and their education and professional development needs in relation to bereavement care. An in-depth qualitative design was adopted using a social constructionist approach as our aims were exploratory and applied. Nineteen GPs (12 women and 7 men) living in Western Australia were interviewed; 14 were based in metropolitan Perth and 5 in rural areas. GPs were invited, via a letter, to participate in a semi-structured interview. The interviews occurred within each GP's workplace or, for the rural GPs, via telephone, and all interviews were digitally audio-recorded and transcribed. Analysis was based upon constant comparison and began as soon as possible after each interview. The data revealed four tensions or opposing views concerning bereavement and bereavement care. These were (1) whether grief is a standardised versus an individual process, (2) the role of the GP in intervening versus promoting resilience, (3) the GP as a broker of services versus a service provider, and (4) the need for formal education and professional development versus 'on-the-job' experiential learning. GPs have a critical role in exploring distress, including grief. However, changes need to be made to ensure GPs have up-to-date knowledge of contemporary theories and approaches. GPs urgently need education both at the undergraduate and postgraduate degree levels, and in continuing professional development. Otherwise GPs will rely on out-dated theories and constructions of grief, which may be detrimental to patient care.


Infantile fibrosarcoma-a clinical and histologic mimicker of vascular malformations: case report and review of the literature.
Infantile fibrosarcoma is a rare soft tissue tumor that usually presents either at birth or in the 1st year of life. Here we describe a case of a 4-month-old female who presented with a congenital right axillary mass. The initial clinical impression was benign vascular/lymphatic malformation. The core biopsy showed a spindle cell lesion with abundant vasculature represented by small vascular channels. However, immunohistochemical analysis did not support a diagnosis of vascular lesion/tumor. Polymerase chain reaction study for ETS Translocation Variant 6/neurotrophic tyrosine kinase receptor, type 3 fusion transcript was positive, and the diagnosis of infantile fibrosarcoma was established. The patient underwent resection of the axillary mass. Microscopic examination of the resection specimen showed numerous vascular channels. Intermixed there were also cellular areas composed of spindle cells similar to those seen in the biopsy material. Molecular studies were repeated and confirmed the diagnosis of infantile fibrosarcoma. Infantile fibrosarcoma has been previously reported in the literature to clinically masquerade as hemangioma. In addition, this case proves that infantile fibrosarcoma could also mimic vascular malformations on clinical, radiologic, and pathologic exams. In fact, the vascular component of the tumor is very unusual in our patient and represents a histologic feature that has not been described before. The case highlights the diagnostic challenges at clinical, radiologic, and pathologic levels in some cases of infantile fibrosarcoma and raises awareness among clinicians and pathologists related to another peculiar pattern that can be encountered in this disease.


Assessing species habitat using Google Street View: a case study of cliff-nesting vultures.
The assessment of a species' habitat is a crucial issue in ecology and conservation. While the collection of habitat data has been boosted by the availability of remote sensing technologies, certain habitat types have yet to be collected through costly, on-ground surveys, limiting study over large areas. Cliffs are ecosystems that provide habitat for a rich biodiversity, especially raptors. Because of their principally vertical structure, however, cliffs are not easy to study by remote sensing technologies, posing a challenge for many researches and managers working with cliff-related biodiversity. We explore the feasibility of Google Street View, a freely available on-line tool, to remotely identify and assess the nesting habitat of two cliff-nesting vultures (the griffon vulture and the globally endangered Egyptian vulture) in northwestern Spain. Two main usefulness of Google Street View to ecologists and conservation biologists were evaluated: i) remotely identifying a species' potential habitat and ii) extracting fine-scale habitat information. Google Street View imagery covered 49% (1,907 km) of the roads of our study area (7,000 km²). The potential visibility covered by on-ground surveys was significantly greater (mean: 97.4%) than that of Google Street View (48.1%). However, incorporating Google Street View to the vulture's habitat survey would save, on average, 36% in time and 49.5% in funds with respect to the on-ground survey only. The ability of Google Street View to identify cliffs (overall accuracy = 100%) outperformed the classification maps derived from digital elevation models (DEMs) (62-95%). Nonetheless, high-performance DEM maps may be useful to compensate Google Street View coverage limitations. Through Google Street View we could examine 66% of the vultures' nesting-cliffs existing in the study area (n = 148): 64% from griffon vultures and 65% from Egyptian vultures. It also allowed us the extraction of fine-scale features of cliffs. This World Wide Web-based methodology may be a useful, complementary tool to remotely map and assess the potential habitat of cliff-dependent biodiversity over large geographic areas, saving survey-related costs.