Fear of hypoglycemia: relationship to hypoglycemic risk and psychological factors.
The major aims of this study were to examine (1) the association between fear of hypoglycemia (FOH) in adults with type 1 diabetes with demographic, psychological (anxiety and depression), and disease-specific clinical factors (hypoglycemia history and unawareness, A1c), including severe hypoglycemia (SH), and (2) differences in patient subgroups categorized by level of FOH and risk of SH. Questionnaires were mailed to 764 patients with type 1 diabetes including the Swedish translation of the Hypoglycemia Fear Survey (HFS) and other psychological measures including the Perceived Stress Scale, Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, Social Phobia Scale, and Fear of Complications Scale. A questionnaire to assess hypoglycemia history was also included and A1c measures were obtained from medical records. Statistical analyses included univariate approaches, multiple stepwise linear regressions, Chi-square t tests, and ANOVAs. Regressions showed that several clinical factors (SH history, frequency of nocturnal hypoglycemia, self-monitoring) were significantly associated with FOH but R (2) increased from 16.25 to 39.2 % when anxiety measures were added to the model. When patients were categorized by level of FOH (low, high) and SH risk (low, high), subgroups showed significant differences in non-diabetes-related anxiety, hypoglycemia history, self-monitoring, and glycemic control. There is a strong link between FOH and non-diabetes-related anxiety, as well as hypoglycemia history. Comparison of patient subgroups categorized according to level of FOH and SH risk demonstrated the complexity of FOH and identified important differences in psychological and clinical variables, which have implications for clinical interventions.


In vivo assessment of the host reactions to the biodegradation of the two novel magnesium alloys ZEK100 and AX30 in an animal model.
Most studies on biodegradable magnesium implants published recently use magnesium-calcium-alloys or magnesium-aluminum-rare earth-alloys.However, since rare earths are a mixture of elements and their toxicity is unclear, a reduced content of rare earths is favorable. The present study assesses the in vivo biocompatibility of two new magnesium alloys which have a reduced content (ZEK100) or contain no rare earths at all (AX30). 24 rabbits were randomized into 4 groups (AX30 or ZEK100, 3 or 6 months, respectively) and cylindrical pins were inserted in their tibiae. To assess the biodegradation μCT scans and histological examinations were performed. The μCT scans showed that until month three ZEK100 degrades faster than AX30, but this difference is leveled out after 6 months. Histology revealed that both materials induce adverse host reactions and high numbers of osteoclasts in the recipient bone. The mineral apposition rates of both materials groups were high. Both alloys display favorable degradation characteristics, but they induce adverse host reactions, namely an osteoclast-driven resorption of bone and a subsequent periosteal formation of new bone. Therefore, the biocompatibility of ZEK100 and AX30 is questionable and further studies, which should focus on the interactions on cellular level, are needed.


A compilation of field surveys on gaseous elemental mercury (GEM) from contrasting environmental settings in Europe, South America, South Africa and China: separating fads from facts.
Mercury is transported globally in the atmosphere mostly in gaseous elemental form (GEM, [Formula: see text]), but still few worldwide studies taking into account different and contrasted environmental settings are available in a single publication. This work presents and discusses data from Argentina, Bolivia, Bosnia and Herzegovina, Brazil, Chile, China, Croatia, Finland, Italy, Russia, South Africa, Spain, Slovenia and Venezuela. We classified the information in four groups: (1) mining districts where this contaminant poses or has posed a risk for human populations and/or ecosystems; (2) cities, where the concentration of atmospheric mercury could be higher than normal due to the burning of fossil fuels and industrial activities; (3) areas with natural emissions from volcanoes; and (4) pristine areas where no anthropogenic influence was apparent. All the surveys were performed using portable LUMEX RA-915 series atomic absorption spectrometers. The results for cities fall within a low GEM concentration range that rarely exceeds 30 ng m(-3), that is, 6.6 times lower than the restrictive ATSDR threshold (200 ng m(-3)) for chronic exposure to this pollutant. We also observed this behavior in the former mercury mining districts, where few data were above 200 ng m(-3). We noted that high concentrations of GEM are localized phenomena that fade away in short distances. However, this does not imply that they do not pose a risk for those working in close proximity to the source. This is the case of the artisanal gold miners that heat the Au-Hg amalgam to vaporize mercury. In this respect, while GEM can be truly regarded as a hazard, because of possible physical-chemical transformations into other species, it is only under these localized conditions, implying exposure to high GEM concentrations, which it becomes a direct risk for humans.


Obesity as a Key Factor Underlying Idiopathic Hyperaldosteronism.
Recently, the relationship between primary aldosteronism (PA) and various metabolic disorders, including obesity, diabetes mellitus, and dyslipidemia, has been discussed. However, in PA, aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) have different etiologies. Our objectives were to clarify differences in obesity and metabolic disorders between APA and IHA and to gain insight in the pathogenesis of IHA. This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan Primary Aldosteronism Study. For comparative analysis, data were also collected from 274 patients with essential hypertension (EHT). We compared prevalences of obesity and metabolic disorders between patients with APA and patients with IHA. Comparisons with sex-, age-, and blood pressure-matched patients with EHT were also performed. Correlations between metabolic parameters and plasma aldosterone concentrations (PACs) in each subtype were analyzed. Analysis of 516 patients with APA and 1015 patients with IHA revealed PACs were significantly higher in patients with APA than patients with IHA. By contrast, after we adjusted for clinical backgrounds, the prevalence of obesity was significantly higher in patients with IHA than in patients with APA or EHT. Although the prevalences of diabetes mellitus and dyslipidemia did not significantly differ between patients with IHA and patients with APA, triglyceride and HbA1c were significantly higher in patients with IHA than in patients with APA. There was no significant correlation between metabolic parameters and PACs in either subtype. Patients with IHA tend to be obese despite lower PACs than in patients with APA. The present results suggest that obesity-related factors contribute to the pathogenesis of IHA.


Enrichment of triadic and terminal cisternae vesicles from rabbit skeletal muscle.
An enriched triad and terminal cisternae preparation was achieved from skeletal muscle through alterations of the differential centrifugation and muscle homogenization protocols. Both yield and specific activity (pmoles of radioligand binding per mg protein) were optimized for (3)H-PN200-110 (transverse tubule marker) and (3)H-ryanodine (terminal cisternae marker) binding sites. By pelleting crude microsomes between 2,000 an 12,000 x g without any rehomogenizations, we improved both the yield and specific activity of transverse tubule and terminal cisternae markers in crude microsomes by approximately 4-fold to 1000-3000 pmoles binding sites (starting material: approximately 400 grams wet weight fast twitch skeletal muscle), with 10-15 pmoles/mg. Rehomogenization of the 1,000 x g pellet, which is typically discarded, allowed recovery of an additional 5000 pmoles PN200-110 binding sites and an additional 8000 pmoles ryanodine binding sites. Crude microsomes from the rehomogenized 1,000 x g pellets typically displayed specific activities of 20-25 pmoles binding/mg for both (3)H-PN200-110 and (3)H-ryanodine. Separation of crude microsomes on a sucrose gradient increased specific activity up to a maximum of 50 pmoles/mg in a specific fraction, a five- to ten-fold increase over standard triadic or terminal cisternae preparations. The mean specific activity for enriched triads was 30-40 pmoles/mg for both PN200-110 and ryanodine in pooled fractions, while pooled fractions of enriched terminal cisternae displayed low (3)H-PN200-110 binding (3-5 pmoles/mg) and high (3)H-ryanodine-specific activity (30-40 pmoles/mg).


Elastic, viscous, and mass load effects on poststroke muscle recruitment and co-contraction during reaching: a pilot study.
Resistive exercise after stroke can improve strength (force-generating capacity) without increasing spasticity (velocity-dependent hypertonicity). However, the effect of resistive load type on muscle activation and co-contraction after stroke is not clear. The purpose of this study was to determine the effect of load type (elastic, viscous, or mass) on muscle activation and co-contraction during resisted forward reaching in the paretic and nonparetic arms after stroke. This investigation was a single-session, mixed repeated-measures pilot study. Twenty participants (10 with hemiplegia and 10 without neurologic involvement) reached forward with each arm against equivalent elastic, viscous, and mass loads. Normalized shoulder and elbow electromyography impulses were analyzed to determine agonist muscle recruitment and agonist-antagonist muscle co-contraction. Muscle activation and co-contraction levels were significantly higher on virtually all outcome measures for the paretic and nonparetic arms of the participants with stroke than for the matched control participants. Only the nonparetic shoulder responded to load type with similar activation levels but variable co-contraction responses relative to those of the control shoulder. Elastic and viscous loads were associated with strong activation; mass and viscous loads were associated with minimal co-contraction. A reasonable, but limited, range of loads was available. Motor control deficits were evident in both the paretic and the nonparetic arms after stroke when forward reaching was resisted with viscous, elastic, or mass loads. The paretic arm responded with higher muscle activation and co-contraction levels across all load conditions than the matched control arm. Smaller increases in muscle activation and co-contraction levels that varied with load type were observed in the nonparetic arm. On the basis of the response of the nonparetic arm, this study provides preliminary evidence suggesting that viscous loads elicited strong muscle activation with minimal co-contraction. Further intervention studies are needed to determine whether viscous loads are preferable for poststroke resistive exercise programs.


Human cancer protein-protein interaction network: a structural perspective.
Protein-protein interaction networks provide a global picture of cellular function and biological processes. Some proteins act as hub proteins, highly connected to others, whereas some others have few interactions. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. Similar or overlapping binding sites should be used repeatedly in single interface hub proteins, making them promiscuous. Alternatively, multi-interface hub proteins make use of several distinct binding sites to bind to different partners. We propose a methodology to integrate protein interfaces into cancer interaction networks (ciSPIN, cancer structural protein interface network). The interactions in the human protein interaction network are replaced by interfaces, coming from either known or predicted complexes. We provide a detailed analysis of cancer related human protein-protein interfaces and the topological properties of the cancer network. The results reveal that cancer-related proteins have smaller, more planar, more charged and less hydrophobic binding sites than non-cancer proteins, which may indicate low affinity and high specificity of the cancer-related interactions. We also classified the genes in ciSPIN according to phenotypes. Within phenotypes, for breast cancer, colorectal cancer and leukemia, interface properties were found to be discriminating from non-cancer interfaces with an accuracy of 71%, 67%, 61%, respectively. In addition, cancer-related proteins tend to interact with their partners through distinct interfaces, corresponding mostly to multi-interface hubs, which comprise 56% of cancer-related proteins, and constituting the nodes with higher essentiality in the network (76%). We illustrate the interface related affinity properties of two cancer-related hub proteins: Erbb3, a multi interface, and Raf1, a single interface hub. The results reveal that affinity of interactions of the multi-interface hub tends to be higher than that of the single-interface hub. These findings might be important in obtaining new targets in cancer as well as finding the details of specific binding regions of putative cancer drug candidates.


Chk2 activation and phosphorylation-dependent oligomerization.
The tumor suppressor gene CHK2 encodes a versatile effector serine/threonine kinase involved in responses to DNA damage. Chk2 has an amino-terminal SQ/TQ cluster domain (SCD), followed by a forkhead-associated (FHA) domain and a carboxyl-terminal kinase catalytic domain. Mutations in the SCD or FHA domain impair Chk2 checkpoint function. We show here that autophosphorylation of Chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably ATM or ATR. Both SQ/TQ sites and non-SQ/TQ sites within the Chk2 SCD can be phosphorylated by active Chk2. Amino acid substitutions in the SCD and the FHA domain impair auto- and trans-kinase activities of Chk2. Chk2 forms oligomers that minimally require the FHA domain of one Chk2 molecule and the SCD within another Chk2 molecule. Chk2 oligomerization in vivo increases after DNA damage, and when damage is induced by gamma irradiation, this increase requires ATM. Chk2 oligomerization is phosphorylation dependent and can occur in the absence of other eukaryotic proteins. Chk2 can cross-phosphorylate another Chk2 molecule in an oligomeric complex. Induced oligomerization of a Chk2 chimera in vivo concomitant with limited DNA damage augments Chk2 kinase activity. These results suggest that Chk2 oligomerization regulates Chk2 activation, signal amplification, and transduction in DNA damage checkpoint pathways.


Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation.
Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference < or =4.3 days) and stool frequency were measured. C4 (7-alpha-hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p <0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p <0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.


Cord blood Streptococcus pneumoniae-specific cellular immune responses predict early pneumococcal carriage in high-risk infants in Papua New Guinea.
In areas where Streptococcus pneumoniae is highly endemic, infants experience very early pneumococcal colonization of the upper respiratory tract, with carriage often persisting into adulthood. We aimed to explore whether newborns in high-risk areas have pre-existing pneumococcal-specific cellular immune responses that may affect early pneumococcal acquisition. Cord blood mononuclear cells (CBMC) of 84 Papua New Guinean (PNG; high endemic) and 33 Australian (AUS; low endemic) newborns were stimulated in vitro with detoxified pneumolysin (dPly) or pneumococcal surface protein A (PspA; families 1 and 2) and compared for cytokine responses. Within the PNG cohort, associations between CBMC dPly and PspA-induced responses and pneumococcal colonization within the first month of life were studied. Significantly higher PspA-specific interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10 and IL-13 responses, and lower dPly-IL-6 responses were produced in CBMC cultures of PNG compared to AUS newborns. Higher CBMC PspA-IL-5 and PspA-IL-13 responses correlated with a higher proportion of cord CD4 T cells, and higher dPly-IL-6 responses with a higher frequency of cord antigen-presenting cells. In the PNG cohort, higher PspA-specific IL-5 and IL-6 CBMC responses were associated independently and significantly with increased risk of earlier pneumococcal colonization, while a significant protective effect was found for higher PspA-IL-10 CBMC responses. Pneumococcus-specific cellular immune responses differ between children born in pneumococcal high versus low endemic settings, which may contribute to the higher risk of infants in high endemic settings for early pneumococcal colonization, and hence disease.


Predictors for the selection of patients for abdominal CT after blunt trauma: a proposal for a diagnostic algorithm.
To select parameters that can predict which patients should receive abdominal computed tomography (CT) after high-energy blunt trauma. Abdominal CT accurately detects injuries of the abdomen, pelvis, and lumbar spine, but has important disadvantages. More evidence for an appropriate patient selection for CT is required. A prospective observational study was performed on consecutive adult high-energy blunt trauma patients. All patients received primary and secondary surveys according to the advanced trauma life support, sonography (focused assessment with sonography for trauma [FAST]), conventional radiography (CR) of the chest, pelvis, and spine and routine abdominal CT. Parameters from prehospital information, physical examination, laboratory investigations, FAST, and CR were prospectively recorded for all patients. Independent predictors for the presence of > or =1 injuries on abdominal CT were determined using a multivariate logistic regression analysis. A total of 1040 patients were included, 309 had injuries on abdominal CT. Nine parameters were independent predictors for injuries on CT: abnormal CR of the pelvis (odds ratio [OR], 46.8), lumbar spine (OR, 16.2), and chest (OR, 2.37), abnormal FAST (OR, 26.7), abnormalities in physical examination of the abdomen/pelvis (OR, 2.41) or lumbar spine (OR 2.53), base excess <-3 (OR, 2.39), systolic blood pressure <90 mm Hg (OR, 3.81), and long bone fractures (OR, 1.61). The prediction model based on these predictors resulted in a R of 0.60, a sensitivity of 97%, and a specificity of 33%. A diagnostic algorithm was subsequently proposed, which could reduce CT usage with 22% as compared with a routine use. Based on parameters from physical examination, laboratory, FAST, and CR, we created a prediction model with a high sensitivity to select patients for abdominal CT after blunt trauma. A diagnostic algorithm was proposed.


Monozygotic twins with familial hypercholesterolemia and high lipoprotein(a) levels leading to identical cardiovascular outcomes: Case report and review of the literature.
Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant disease that leads to premature cardiovascular disease (CVD). Since monozygotic twins share the intrauterine environment and have the same age and gene profile, they could represent a very special resource for the investigation of the causes and the natural course of FH. This report is a description of 36-year-old monozygotic twin brothers with almost identical early coronary artery involvement due to FH concomitant with high lipoprotein(a) (Lpa) levels and a review of the literature. Sequence analysis revealed that the twins were homozygous for the LDLR c.1060+10G>A (rs12710260) mutation and heterozygous for the LDLR c.542C>T (rs557344672) mutations. Both were also homozygous for the c.1060+7T>C (rs2738442) and c.1586+53A>G (rs1569372) mutations in the LDLR gene as well as c.4265A>T (rs568413) mutations in the APOB gene. In the literature, there are 7 twin cases with reported FH, but none with high Lpa levels. The HoFH twins in this case report had lower low-density lipoprotein (LDL) cholesterol levels than expected (before treatment 204 and 223 mg/dL), with almost identical coronary involvement. Both had an extremely high Lpa level (308 and 272 nmol/L) with a very low coronary calcium score (16 AU) and a good response to statins (>60%). There was a history of the first CVD event occurring at nearly the same age (32-34 years) in the family. This could be an important aspect of FH families as a result of the similar timing of cumulative LDL exposure exceeding the threshold of CVD events. In conclusion, this first report of monozygotic HoFH twins with elevated Lpa levels and almost identical early coronary artery involvement at the same age provides evidence to substantiate the hypothesis of lifetime cholesterol burden/exposure.


[Non-erosive gastroesophageal reflux disease. Incidence of clinical forms, characteristics of esophageal exposure to acid and symptomatic correlations].
It is estimated that up to 70% of community-based patients with heartburn have no evidence of esophageal mucosal injury or non-erosive gastroesophageal reflux disease (NERD). Studies in NERD patients using esophageal pH monitoring and symptom index (SI) have suggested different subgroups or clinical forms. Our aim was to investigate frequency of different subgroups of patients with NERD according to esophageal pH-monitoring parameters and SI, and to determine esophageal acid exposure characteristics and the relationship between symptoms and acid reflux in NERD. Patients with heartburn at least 3 times per week during 12 weeks during the last year and negative upper GI endoscopy were studied. All patients were submitted to 24 h esophageal pH-metry and SI was calculated. Patients were classified into three groups: group I, patients with abnormal pH-metry; group II, patients with normal pH-metry and positive SI (> or = 50%), and group III, patients with normal pH-metry and negative SI (< 50%). Total number of reflux episodes, length of episode, % time pH < 4, and Johnson-DeMeester score were evaluated. Three hundred patients, 206 women and 94 men, were included. A total of 137 (46%) were classified in group I, 62 (21%) in group II, and 101 (33%) in group III. There were no significant differences in gender and age among groups. All pH parameters were significantly higher in group I. In group II, there was good correlation between heartburn and acid reflux. Esophageal acid exposure in group III was minimal and there was no relationship among symptoms and acid reflux episodes. Subjects with NERD represent a heterogeneous group of patients. Three subgroups of patients with NERD were identified by pH-metry and SI; a) patients with abnormal acid exposure; b) patients with hypersensitive esophagus (heartburn with physiologic amounts of acid reflux), and c) patients with no correlation between symptoms and acid reflux.


Thermally stable antireflective coatings based on nanoporous organosilicate thin films.
Thermally stable nanoporous organosilicate thin films were realized by the microphase separation of pore-generating polymers mixed with an organosilicate matrix to be antireflective coatings (ARCs), for which a thin film with a refractive index (n) of 1.23 for zero reflection is required. The refractive index of such nanoporous organosilicate films can be tuned from 1.39 down to 1.23 by incorporating nanopores within the films. With a nanoporous single layer with n approximately 1.23, the light transmittance of the glass above 99.8% was achieved in the visible range (lambda approximately 550 nm). To overcome the limitation on the narrow wavelength for high transmittance imposed by a single antireflective nanoporous thin film, bilayer thin films with different refractive indices were prepared by placing a high refractive index layer with a refractive index of 1.45 below the nanoporous thin film. UV-vis transmittance of a glass coated with the bilayer films was compared with nanoporous single-layer films and it is demonstrated that the novel broadband antireflection coatings in a wide range of visible wavelength can be easily obtained by the organosilicate bilayer thin films described in this study. Also, ARCs developed in this study demonstrate excellent AR durability owing to the hydrophobic nature of the organosilicate matrix.


Autosomal and X-linked single nucleotide polymorphisms reveal a steep Asian-Melanesian ancestry cline in eastern Indonesia and a sex bias in admixture rates.
The geographical region between mainland Asia and New Guinea is characterized by numerous small islands with isolated human populations. Phenotypically, groups in the west are similar to their neighbours in mainland Southeast Asia, eastern groups near New Guinea are similar to Melanesians, and intervening populations are intermediate in appearance. A long-standing question is whether this pattern primarily reflects mixing between groups with distinct origins or whether natural selection has shaped this range of variation by acting differentially on populations across the region. To address this question, we genotyped a set of 37 single nucleotide polymorphisms that are evolutionarily independent, putatively neutral and highly informative for Asian-Melanesian ancestry in 1430 individuals from 60 populations spanning mainland Asia to Melanesia. Admixture analysis reveals a sharp transition from Asian to Melanesian genetic variants over a narrow geographical region in eastern Indonesia. Interestingly, this admixture cline roughly corresponds to the human phenotypic boundary noted by Alfred Russell Wallace in 1869. We conclude that this phenotypic gradient probably reflects mixing of two long-separated ancestral source populations-one descended from the initial Melanesian-like inhabitants of the region, and the other related to Asian groups that immigrated during the Paleolithic and/or with the spread of agriculture. A higher frequency of Asian X-linked markers relative to autosomal markers throughout the transition zone suggests that the admixture process was sex-biased, either favouring a westward expansion of patrilocal Melanesian groups or an eastward expansion of matrilocal Asian immigrants. The matrilocal marriage practices that dominated early Austronesian societies may be one factor contributing to this observed sex bias in admixture rates.


In vivo distribution of human milk leucocytes after ingestion by newborn baboons.
The in vivo distribution of enterally administered human milk leucocytes labelled with indium hydroxyquinoline (111In) was studied in premature baboons. The animals were killed at 72 hours of age and tissue samples examined for radioactivity. Maximum activity was found in the luminal contents, and activity in the liver and spleen was higher than in bone marrow, the site where free isotope is normally deposited. These findings suggest that some intact milk leucocytes may cross from the gastrointestinal tract into the neonatal circulation. Also the high activity in gastrointestinal tissue that had been washed several times indicates that leucocytes adhere to mucosa or lie intramurally. We speculate that the presence of leucocytes in the gastrointestinal tract 60 hours after a single breast feed can provide an important defence mechanism against infection.


Environmental Determinants of Insufficient Sleep and Sleep Disorders: Implications for Population Health.
Sleep is important for overall health and well-being. Insufficient sleep and sleep disorders are highly prevalent among adults and children and therefore a public health burden, particularly because poor sleep is associated with adverse health outcomes. Emerging evidence has demonstrated that environmental factors at the household- and neighborhood-level can alter healthy sleep. This paper will (1) review recent literature on the environmental determinants of sleep among adults as well as children and adolescents; and (2) discuss the opportunities and challenges for advancing research on the environment and sleep. Epidemiologic research has shown that social features of environments, family, social cohesion, safety, noise, and neighborhood disorder can shape and/or impact sleep patterns; and physical features such as light, noise, traffic, pollution, and walkability can also influence sleep and is related to sleep disorders among adults and children. Prior research has mainly measured one aspect of the environment, relied on self-reported sleep, which does not correlate well with objective measures, and investigated cross-sectional associations. Although most studies are conducted among non-Hispanic white populations, there is growing evidence that indicates that minority populations are particularly vulnerable to the effects of the environment on insufficient sleep and sleep disorders. There is clear evidence that environmental factors are associated with insufficient sleep and sleep disorders. However, more research is warranted to evaluate how and which environmental factors contribute to sleep health. Interventions that target changes in the environment to promote healthy sleep should be developed, tested, and evaluated as a possible pathway for ameliorating sleep health disparities and subsequently health disparities.


Improved method for concentration of Giardia, Cryptosporidium, and poliovirus from water.
Methods for the concentration of enteric viruses and the protozoan parasites, Giardia and Cryptosporidium, from drinking water currently require the use of two different types of filters. Electropositive or electronegative microporous filters (0.2-0.45 microm nominal porosity) are used for the collection of enteroviruses, while polypropylene spun-fiber filters (1 microm porosity) and small pleated cartridge filters are used for the collection of protozoan parasites from water. Since the filter mechanically traps the protozoa by size exclusion, a microporous filter with an appropriately small nominal porosity could possibly be used for co-collection of both protozoa and enteroviruses. This study compared the concentration efficiencies of a polypropylene fiber cartridge (DPPPY) filter and two different microporous filters (Filterite and IMDS) with poliovirus (type 1), with respect to their ability to concentrate Giardia and Cryptosporidium from water. Giardia cysts and Cryptosporidium oocysts were added to 4001 of either tap water or tertiary treated wastewater and passed through the test filter. The protozoa were eluted from the polypropylene filter by hand-washing in a detergent solution. Viruses and protozoa were eluted from the microporous filter by two consecutive back-washes with a 1.5% beef extract, 0.1% Tween 80 solution. The eluent was then centrifuged to remove the parasites and the supernatant assayed for viruses. The overall efficiency was greater for the Filterite filter (40.4% for Giardia; 36.6% for Cryptosporidium) when compared to the spun fiber filter (10.1% for Giardia; 16.0% for Cryptosporidium). The Filterite filters were easier and faster to process than the polypropylene spun fiber filters. There was no significant difference in the recovery of protozoa from 1MDS and DPPPY filters. Co-collection of viruses and protozoan parasites from water onto the same filter is possible and can reduce the time and cost of routine water monitoring.


Telomerase immortalization of human myometrial cells.
Several strategies have been described for the primary culture of human myometrial cells. However, primary cultures of myometrial cells have a limited life span, making continual tissue acquisition and cell isolation necessary. Recent studies have demonstrated that cell culture life span is related to chromosomal telomere length, and cellular senescence results from progressive telomere shortening and the lack of telomerase expression. Transfection of cells with expression vectors containing the human telomerase reverse transcriptase (hTERT) maintains telomere length and effectively gives normal cells an unlimited life span in culture. In addition, hTERT extends the life span of cultured cells far beyond normal senescence without causing neoplastic transformation. In the present study, we developed a cell line from hTERT-infected myometrial cells (hTERT-HM). Cells were isolated from myometrial tissue obtained from women undergoing hysterectomy, and retroviral infection was used to express the catalytic subunit of telomerase in myometrial cells. Cells expressing hTERT have been in continuous culture for >10 mo, whereas the control culture senesced after approximately 2 mo. Telomerase activity was monitored in cells with a polymerase chain reaction-based telomerase activity assay. Telomerase-expressing cells contained mRNA for alpha smooth muscle actin, smoothelin, oxytocin receptor, and estrogen receptor alpha, but the estrogen receptor beta receptor was lost. Immunoblotting analysis identified the expression of calponin, caldesmon, alpha smooth muscle actin, and oxytocin receptor. Although estrogen receptor expression was below the level of detection with immunoblotting, transfection experiments performed with reporter constructs driven by estrogen response elements demonstrated estrogen responsiveness in the hTERT-HM. In addition, treatment of hTERT-HM with oxytocin caused a concentration-dependent increase in intracellular calcium levels, confirming the presence of functional oxytocin receptors. Myometrial cells immortalized with hTERT retained markers of differentiation that are observed in primary cultures of smooth muscle cells. The expression of various smooth muscle/myometrium cell markers suggests that these cells may be an appropriate model system to study certain aspects of human myometrial function.


Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic markings.
COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, that regulates the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic markings in leukocytes favorably regulates central components of COVID-19 physiopathology.


The position of the euploid blastocyst in the uterine cavity influences implantation.
Does the position of the euploid blastocyst in the uterine cavity upon transfer, measured as distance in millimetres (mm) from the fundus (DFF) to the air bubble, influence implantation potential? A total of 507 single/double euploid frozen embryo transfer (FET) cycles at blastocyst stage were included retrospectively between March 2017 and November 2018 at a single centre. The patients were on average 33.3 years old. The FET were performed in natural cycles (n = 151) or hormone replacement therapy cycles (n = 356). Of the 507 transfers, 370 (73.0%) resulted in a pregnancy, defined as human chorionic gonadotrophin concentration over 15 mIU/ml, and 341 (67.3%) in a clinical pregnancy, with an implantation rate of 62.0% and ongoing pregnancy rate of 59.6% (302/507). When comparing the number of embryos transferred, the pregnancy rate, clinical pregnancy rate and ongoing pregnancy rate were significantly higher after double-embryo transfer (DET) (P = 0.002: P < 0.001 and P = 0.002). The quality of the blastocyst in the single-embryo transfer group had a positive effect on the pregnancy rate (A versus B, P = 0.016; A versus C, P = 0.003) and clinical pregnancy rate (A versus C, P = 0.013). After performing a multivariate logistic regression analysis to consider the effect of all explanatory variables, a negative effect between DFF and pregnancy (P = 0.001), clinical pregnancy (P = 0.001) and ongoing pregnancy (P = 0.030) was found. When all variables remained constant, an increase of 1 mm of DFF changed the odds of pregnancy by 0.882, of clinical pregnancy by 0.891 and of ongoing pregnancy by 0.925. No significant effect of DFF was found on the miscarriage outcome (P = 0.089). The depth of blastocyst replacement inside the uterine cavity may influence the pregnancy, clinical pregnancy and ongoing pregnancy rates and should be considered as an important factor to improve the success of IVF cycles.


Compartment Pressures in Children With Normal and Fractured Forearms: A Preliminary Report.
Acute compartment syndrome (ACS) can lead to irreversible damage if fasciotomy is not performed in a timely manner. Needle manometry is a tool to confirm suspected ACS. The threshold for compartment pressures that can be tolerated has been debated. The aim of this study is to assess the normal compartment pressures in noninjured forearms of children. Further, we sought to quantify the maximum tolerable compartment pressures in fractured forearms of children, thus establishing a baseline and providing guidance in evidence-based decision making to evaluate children with suspected ACS. This prospective study included children up to the age of 16 years with forearm fractures that needed reduction with or without osteosynthesis. Between June 2009 and March 2013, 41 children were included. Mean age was 9.25 years (range, 4 to 15.4 y). We used needle manometry to measure the pressures in the superficial and deep volar as well as in the dorsal compartments (DCs) on both the forearms. The mean pressures between compartments in healthy versus injured arms were analyzed using a 1-sided, paired t test. On the injured side, the mean compartment pressure was 19.12 mm Hg (range, 3 to 49 mm Hg) in the deep volar compartment, 15.56 mm Hg (range, 5 to 37 mmHg) in the DC, and 14.8 mm Hg (range, 2 to 35 mm Hg) in the superficial volar compartment. On the noninjured side, the mean compartment pressure was 12.9 mm Hg (range, 6 to 31 mm Hg) in the DC, 10.22 mm Hg (range, 3 to 22 mm Hg) in the deep volar compartment, and 9.66 mm Hg (range, 3 to 21 mm Hg) in the superficial volar compartment. We measured an absolute compartment pressure of >30 mm Hg in 15 patients on the fractured side. Three of them had an absolute compartment pressure of >45 mm Hg. Only 1 had ACS. This patient underwent fasciotomy and was excluded for further analysis. On follow-up (mean, 24.84 mo), no patient was found to have any sequelae of ACS. This is the first study to report normal compartment pressure measurements in noninjured forearms and in fractured forearms without clinical suspicion of ACS in children.The mean compartment pressure measured in the deep volar compartment (DVC) in healthy children was 10.22 mm Hg (range, 3 to 22 mm Hg) and therefore slightly higher than in adults. Some children with fractures tolerated absolute compartment pressures >30 mm Hg without clinical signs of ACS. Fasciotomy in children under close observation could eventually be delayed despite surpassing the accepted pressure limits for adults. Level I-prognostic.


Body mass index and type 2 diabetes in Thai adults: defining risk thresholds and population impacts.
Body mass index (BMI) cut-off values (>25 and >30) that predict diabetes risk have been well validated in Caucasian populations but less so in Asian populations. We aimed to determine the BMI threshold associated with increased type 2 diabetes (T2DM) risk and to calculate the proportion of T2DM cases attributable to overweight and obesity in the Thai population. Participants were those from the Thai Cohort Study who were diabetes-free in 2005 and were followed-up in 2009 and 2013 (n = 39,021). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the BMI-T2DM association. We modelled non-linear associations using restricted cubic splines. We estimated population attributable fractions (PAF) and the number of T2DM incident cases attributed to overweight and obesity. We also calculated the impact of reducing the prevalence of overweight and obesity on T2DM incidence in the Thai population. Non-linear modelling indicated that the points of inflection where the BMI-T2DM association became statistically significant compared to a reference of 20.00 kg/m2 were 21.60 (OR = 1.27, 95% CI 1.00-1.61) and 20.03 (OR = 1.02, 95% CI 1.02-1.03) for men and women, respectively. Approximately two-thirds of T2DM cases in Thai adults could be attributed to overweight and obesity. Annually, if prevalent obesity was 5% lower, ~13,000 cases of T2DM might be prevented in the Thai population. A BMI cut-point of 22 kg/m2, one point lower than the current 23 kg/m2, would be justified for defining T2DM risk in Thai adults. Lowering obesity prevalence would greatly reduce T2DM incidence.


Update on riboflavin and multiple sclerosis: a systematic review.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Riboflavin plays an important role in myelin formation, and its deficiency is implicated as a risk factor for multiple sclerosis. Here, we systematically reviewed the literature concerning the health benefits of riboflavin on MS. The literature recorded within four main databases, including relevant clinical trials, experimental, and case-control studies from 1976 to 2017 were considered. Both human and animal studies were included for review, with no restrictions on age, gender, or ethnicity. Experimental studies demonstrated that riboflavin deficiency triggers neurologic abnormalities related to peripheral neuropathies such as demyelinating neuropathy. Moreover, randomized controlled trials (RCT) and case-control studies in which MS patients received riboflavin supplementation or had higher dietary riboflavin intake showed improvements in neurological motor disability. Riboflavin is a cofactor of xanthine oxidase and its deficiency exacerbates low uric acid caused by high copper levels, leading to myelin degeneration. The vitamin additionally plays a significant role in the normal functioning of glutathione reductase (GR) as an antioxidant enzyme, and conditions of riboflavin deficiency lead to oxidative damage. Riboflavin promotes the gene and protein levels of brain-derived neurotrophic factor (BDNF) in the CNS of an animal model of MS, suggesting that BDNF mediates the beneficial effect of riboflavin on neurological motor disability. Research to date generally supports the role of riboflavin in MS outcomes. However, further observational and interventional studies on human populations are warranted to validate the effects of riboflavin.


Population pharmacokinetic assessment of the effect of food on piperaquine bioavailability in patients with uncomplicated malaria.
Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n=15) and without (n=15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.


Prevalence of hypertrophic cardiomyopathy in a population-based sample of American Indians aged 51 to 77 years (the Strong Heart Study).
Recognition of the frequency with which hypertrophic cardiomyopathy (HC) occurs in the general population is critical to understanding its demographics and public health implications. However, few data are available for estimating HC prevalence in large populations of different age strata and ethnic or racial groups. The Strong Heart Study is a prospective, population-based epidemiologic survey of cardiovascular disease in residents of 13 geographically diverse American Indian communities. The study population was comprised of 3,501 subjects with echocardiograms performed in 1993 and 1995 to determine the prevalence of HC in middle-aged and older adult populations. Evidence of the HC phenotype was present in 8 previously undiagnosed patients (0.23%; 2 of 1,000) based on a left ventricular (LV) wall thickness >/=15 mm and a nondilated cavity that was not associated with another cardiac disease and was sufficient to produce the magnitude of hypertrophy evident. Ages were 51 to 77 years (mean 64 +/- 9). Four subjects were men and 4 were women, with prevalences by gender of 0.3% (3 of 1,000) and 0.18% (1.8 of 1,000), respectively. Maximum LV thicknesses were 19 to 29 mm (mean 21 +/- 3). Two subjects had mitral valve systolic anterior motion, which was sufficient to produce LV outflow obstruction at rest in 1 patient. Different electrocardiographic abnormalities were present in 5 subjects. In conclusion, clinically unrecognized HC was present in 1:500 of an aging American Indian cohort. This prevalence was similar to that reported in other general populations comprised of younger subjects of other races, offering evidence that HC is a relatively common genetic disease with widespread occurrence within the United States.


An electronic colonoscopy record system enables detailed quality assessment and benchmarking of an endoscopic service.
Competence in colonoscopy, which is a technically difficult procedure, requires adequate exposure to it and the maintenance of a detailed logbook. Without an electronic record this is difficult to achieve. By implementing an electronic medical record system we aimed to perform a detailed quality assessment audit of colonoscopy, to benchmark our results and generate accurate logbooks for individual endoscopists. We reviewed the prospectively maintained Hybrid Electronic Medical Registry (HEMR). Colonoscopies performed between March 2013 and March 2014 were reviewed, and for competency, quality metrics were derived from the guidelines of the American Society of Gastroenterology. A total of 843 colonoscopies were performed. Seven hundred and seventy procedures were performed by three staff endoscopists who each performed over the required 150 procedures annually (n=197, 338 and 235). The remaining 73 (8.7%) were performed by other staff. In 105 cases (12.5%), bowel preparation was deemed to be inadequate, which caused the procedure to be abandoned in 34 cases. A total of 64 cases were deemed to be incomplete because of obstructing lesions (n=26), extensive diverticulosis (n=4), technical difficulty (n=31) and patient discomfort (n=3). There were two complications recorded: perforation (n=1) and bleeding (n=1). The HEMR system enabled the audit of experiences with colonoscopy in our institution. Our results are broadly compatible with the international literature and with a number of guidelines. The development of an electronic record system is a major advance, as it enables meaningful benchmarking and the generation of accurate procedural logbooks.


Attitudes towards continuous professional development: a study of pharmacists in Lebanon.
To investigate the views and assess motivation, attitudes of pharmacists in Lebanon towards mandatory continuous education (CE), its transition to Continuous Professional Development (CPD), and identify barriers to participation in CPD. A cross-sectional observational study, conducted between February and May 2017, enrolled 591 pharmacists. The questionnaire used in this study was developed after an extensive literature review and based on previous similar studies in different countries. Half of the pharmacists who completed the questionnaire agreed that all the factors that were mentioned in the questionnaire motivated completing CPD, whereas 55.4% felt confident that CPD meets their needs. 78.4% felt confident in their abilities to assess what they have learned. 71.6% felt confident in their abilities to assess what additional CPD activity may be necessary. The majority of the pharmacists agreed that accessibility of group learning activities (location/distance) (69.6%), job restrictions (76.3%) and lack of time (80.6%) were the most essential barriers against participation in CPD. Motivation was significantly and positively correlated with attitude (r= 0.718), but negatively correlated with barriers (r= -0.243). Attitude was significantly and negatively correlated with barriers (r= -0.120). Our findings contribute to informing the forward pathway for the profession. Attitude and motivation to CPD were positive in this study. Accessibility of group learning activities due to distance and location, job restrictions and lack of time were the major barriers to participation in CPD. Potential solutions can be sought to address these issues.


Variation in immunoglobulin G and albumin concentrations during lumbar CSF removal: a reappraisal.
We studied the variation in immunoglobulin G (IgG) and albumin concentrations in serial sampling of the first 25 ml of CSF during lumbar puncture (LP). A linear decremental gradient averaged 15% for both IgG and albumin. Both direction and magnitude of the gradient were unaffected by the position of the patient. In 12 patients with MS, the CSF IgG: albumin quotient was 5.5% greater when computed from the last aliquot, but this difference was not significant. These protein gradients affect the absolute concentrations but arae not likely to affect the interpretation of immunoglobulin indices or electrophoresis patterns.


Reducing Iodine Contrast Volume in CT Angiography of the Abdominal Aorta Using Integrated Tube Potential Selection and Weight-Based Method Without Compromising Image Quality.
The purpose of this study is to determine whether image quality was maintained when a weight-based protocol incorporating tube potential selection was used to select lower iodine contrast volumes for aortic CT angiography (CTA). Patients with potentially decreased renal function underwent CTA performed with the iodinated contrast volume determined using a table incorporating different tube potentials and patient weights. The image quality of CTA examinations performed with a reduced iodine volume (hereafter known as "low-iodine CTA examinations"), internal control CTA examinations (i.e., prior examinations), and size-matched control CTA examinations was evaluated in separate reading sessions conducted by three vascular radiologists who were blinded as to the contrast volume and tube potential used. Side-by-side unblinded comparison of the examinations was also performed. Aortic attenuation and the contrast-to-noise ratio were measured. Comparisons were performed using the Wilcoxon signed rank test. Fifty low-iodine CTA examinations, 36 internal control CTA examinations, and 50 size-matched control CTA examinations were performed. Contrast volumes were 63% lower when the protocol based on tube potential and patient weight was used (mean contrast volume, 49 mL for low-iodine CTA vs 133 mL for internal control CTA and 138 mL for size-matched control CTA). The mean volume CT dose index was 15.1 mGy for low-iodine CTA versus 18.8 mGy for internal control CTA (p < 0.001), and 15.3 mGy for low-iodine CTA versus 17.1 mGy for size-matched control CTA (p = 0.11). Of the image quality and diagnostic confidence evaluations for low-iodine CTA examinations, over 97% had acceptable image quality and diagnostic confidence for blinded (50/50) and unblinded (35/36) comparisons. Aortic attenuation was similar between groups (p = 0.13-0.71). A weight-based protocol that incorporates tube potential selection allows the use of substantially lower volumes of iodinated contrast material in aortic CTA while maintaining acceptable image quality.


Multiple testing in disease mapping and descriptive epidemiology.
The problem of multiple testing is rarely addressed in disease mapping or descriptive epidemiology. This issue is relevant when a large number of small areas or diseases are analysed. Control of the family wise error rate (FWER), for example via the Bonferroni correction, is avoided because it leads to loss of statistical power. To overcome such difficulties, control of the false discovery rate (FDR), the expected proportion of false rejections among all rejected hypotheses, was proposed in the context of clinical trials and genomic data analysis. FDR has a Bayesian interpretation and it is the basis of the so called q-value, the Bayesian counterpart of the p-value. In the present work, we address the multiplicity problem in disease mapping and show the performance of the FDR approach with two real examples and a small simulation study. The examples consider testing multiple diseases for a given area or multiple areas for a given disease. Using unadjusted p-values for multiple testing, an inappropriately large number of areas or diseases at altered risk are identified, whilst FDR procedures are appropriate and more powerful than the control of the FWER with the Bonferroni correction. We conclude that the FDR approach is adequate to screen for high/low risk areas or for disease excess/deficit and useful as a complementary procedure to point estimates and confidence intervals.


Cyamemazine decreases ethanol intake in rats and convulsions during ethanol withdrawal syndrome in mice.
The effect of cyamemazine a dopamine D2 receptor antagonist on voluntary ethanol consumption in rats and on ethanol withdrawal in mice was examined. Male Sprague-Dawley rats were tested in a free choice (water and 10% ethanol) experiment and consumed 5 g/kg ethanol daily. Rats were treated daily IP with cyamemazine (0.5, 1, or 2 mg/kg) or acamprosate (100 mg/kg) during 2 weeks. Both acamprosate and 1 mg/kg cyamemazine significantly decreased ethanol intake by 45% without affecting either fluid or food intake. The lowest dose of cyamemazine had no effect on alcohol intake but increased food intake. The highest dose had no effect on any variables. During the post-treatment period, only 1 mg/kg cyamemazine decreased both ethanol and fluid intakes. Mice were made dependent on alcohol using a chocolate fluid diet containing increasing concentrations of alcohol and withdrawn after 9 days. Mice were treated with cyamemazine (1 or 0.5 mg/kg, respectively) or with the same doses of lorazepam acutely on the day of withdrawal or chronically (during alcohol treatment). Both chronic and acute cyamemazine and lorazepam treatments decreased convulsions during ethanol withdrawal. Both acute treatments decreased locomotor activity in control and alcohol dependent mice. Chronic treatment had no effect on locomotor activity. We suggest that cyamemazine could reduce alcohol consumption by antagonizing the activation of the dopaminergic pathways during the induction of alcohol dependence. The action of cyamemazine on 5-HT3 receptors could also explain its effect on alcohol convulsions during withdrawal convulsions.


Improving sequence-based modeling of protein families using secondary-structure quality assessment.
Modeling of protein family sequence distribution from homologous sequence data recently received considerable attention, in particular for structure and function predictions, as well as for protein design. In particular, direct coupling analysis, a method to infer effective pairwise interactions between residues, was shown to capture important structural constraints and to successfully generate functional protein sequences. Building on this and other graphical models, we introduce a new framework to assess the quality of the secondary structures of the generated sequences with respect to reference structures for the family. We introduce two scoring functions characterizing the likeliness of the secondary structure of a protein sequence to match a reference structure, called Dot Product and Pattern Matching. We test these scores on published experimental protein mutagenesis and design dataset, and show improvement in the detection of nonfunctional sequences. We also show that use of these scores help rejecting nonfunctional sequences generated by graphical models (Restricted Boltzmann Machines) learned from homologous sequence alignments. Data and code available at https://github.com/CyrilMa/ssqa. Supplementary data are available at Bioinformatics online.


Course of coccidioidomycosis in intratracheally infected guinea pigs.
Two hundred Hartley-inbred guinea pigs were infected intratracheally with 50 viable arthrospores of Coccidioides immitis. At weeks 1 through 10 postinfection, groups of 20 guinea pigs were assayed for skin test, macrophage migration inhibitory factor (MIF), and lymphocyte transformation (LT) responses to coccidioidin. Forty-eight hours after skin testing and just before MIF and LT assays, blood was obtained for complement-fixing (CF) antibody titers and the animals were autopsied to assess the extent of fungal dissemination. Immunological assays established that skin tests and MIF responses converted within 3 weeks of infection. LT responses were not demonstrable until week 5. Dissemination of C. immitis to the liver or spleen was an early event, with 21% of guinea pigs positive by week 2 and 70% positive by week 5. CF antibody titers were demonstrable at week 5, increased logarithmically through week 7, then increased at a slower rate thereafter. Concomitant with the decreased rate of antibody production, guinea pigs began to clear C. immitis from their extrapulmonary tissues. Skin test responses peaked at 6 weeks postinfection when CF antibody titers were less than or equal to 1:16 and then plateaued with increased CF titers. Although this overall immunological profile is consistent with the disease in humans, there was not a direct correlation between CF antibody titer and dissemination to the liver or spleen, nor was there an inverse correlation between CF antibody titers and skin test or MIF responses. Rather, CF antibody titers and cell-mediated immune responses were equally demonstrable in guinea pigs with disseminated or nondisseminated disease.


Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide-binding proteins and second messengers.
The cloning and functional expression of five mammalian muscarinic acetylcholine receptor genes (m1-m5) has revealed that m1, m3, and m5 primarily couple to stimulation of phosphoinositide (PI) turnover, whereas m2 and m4 are strongly linked to inhibition of adenylate cyclase, albeit not exclusively. To identify the structural domains responsible for this functional specificity, cDNAs encoding chimeric m2/m3 receptors were constructed. The abilities of these receptors to mediate stimulation of PI hydrolysis and inhibition of prostaglandin E2-stimulated cAMP accumulation, as well as the pertussis toxin (PTX) sensitivity of these responses, were examined after stable expression in mouse A9 L cells. Substitution of the putative third cytoplasmic loop (i3) of m2 with the corresponding m3 sequence resulted in a chimeric receptor that, similar to m3, stimulated PI breakdown by a PTX-insensitive mechanism but did not inhibit adenylate cyclase. Conversely, a chimeric m3 receptor containing the i3 domain of m2 showed the same functional profile as m2 (i.e., inhibition of adenylate cyclase and weak stimulation of PI turnover by a PTX-sensitive mechanism), indicating that the i3 loop is sufficient to determine coupling selectivity. Similarly, exchange of a short N-terminal segment of i3 (16 or 17 amino acids) between m2 and m3 resulted in chimeric receptors that gained the ability to mediate the functional responses of the wild-type receptor from which the segment was derived, although with substantially reduced efficiency. However, the chimeric m2 receptor containing the 17-amino acid m3 sequence in the N-terminal portion of i3 retained its ability to inhibit adenylate cyclase. Carbachol binding studies involving the use of the GTP analog 5'-guanylyl imidodiphosphate and PTX-pretreated cells generally correlated well with the functional findings. Our data indicate that the N-terminal portion of i3 is a sufficient but not the exclusive determinant of coupling selectivity displayed by the various muscarinic receptors.


Genetic affinities between endogamous and inbreeding populations of Uttar Pradesh.
India has experienced several waves of migration since the Middle Paleolithic. It is believed that the initial demic movement into India was from Africa along the southern coastal route, approximately 60,000-85,000 years before present (ybp). It has also been reported that there were two other major colonization which included eastward diffusion of Neolithic farmers (Elamo Dravidians) from Middle East sometime between 10,000 and 7,000 ybp and a southern dispersal of Indo Europeans from Central Asia 3,000 ybp. Mongol entry during the thirteenth century A.D. as well as some possible minor incursions from South China 50,000 to 60,000 ybp may have also contributed to cultural, linguistic and genetic diversity in India. Therefore, the genetic affinity and relationship of Indians with other world populations and also within India are often contested. In the present study, we have attempted to offer a fresh and immaculate interpretation on the genetic relationships of different North Indian populations with other Indian and world populations. We have first genotyped 20 tetra-nucleotide STR markers among 1800 north Indian samples of nine endogamous populations belonging to three different socio-cultural strata. Genetic distances (Nei's DA and Reynold's Fst) were calculated among the nine studied populations, Caucasians and East Asians. This analysis was based upon the allelic profile of 20 STR markers to assess the genetic similarity and differences of the north Indian populations. North Indians showed a stronger genetic relationship with the Europeans (DA 0.0341 and Fst 0.0119) as compared to the Asians (DA 0.1694 and Fst - 0.0718). The upper caste Brahmins and Muslims were closest to Caucasians while middle caste populations were closer to Asians. Finally, three phylogenetic assessments based on two different NJ and ML phylogenetic methods and PC plot analysis were carried out using the same panel of 20 STR markers and 20 geo-ethnic populations. The three phylogenetic assessments revealed that north Indians are clustering with Caucasians. The genetic affinities of Indians and that of different caste groups towards Caucasians or East Asians is distributed in a cline where geographically north Indians and both upper caste and Muslim populations are genetically closer to the Caucasians.


Racial differences in survival from gynecologic cancer.
To determine whether survival from gynecologic cancer is different between African-American and white patients at an inner-city hospital with both a large clinic and a private service. We studied 538 patients (89 African American, 449 white) diagnosed with cervical, uterine, or ovarian cancer at a single institution from January 1, 1989 through December 31, 1993. Information was obtained on age, stage, site of disease, histology, and type of health insurance (public or commercial). Insurance coverage was used as a proxy for socioeconomic status. Overall survival was estimated by the method of Kaplan and Meier and compared by the log-rank test. Cox proportional hazard modeling was used to evaluate the effects of multiple factors on survival. African-American patients were significantly older and were more likely to have cervical cancer and public insurance than white patients. Overall survival was worse for African-American patients than for white patients (P < .05). However, stage for stage, there was no significant difference in survival between the groups. There was also no difference when patients were grouped by insurance status. African Americans had a significantly worse survival for cervical cancer than whites, and African-American patients older than 65 years had a worse survival than whites of similar age. On multivariate analysis, only stage and insurance coverage were significant predictors of survival. African-American patients with gynecologic cancer at our institution have worse overall survival than white patients. The survival difference seems to be due predominantly to differences in socioeconomic status and stage at diagnosis.


A systematic analysis of cell cycle regulators in yeast reveals that most factors act independently of cell size to control initiation of division.
Upstream events that trigger initiation of cell division, at a point called START in yeast, determine the overall rates of cell proliferation. The identity and complete sequence of those events remain unknown. Previous studies relied mainly on cell size changes to identify systematically genes required for the timely completion of START. Here, we evaluated panels of non-essential single gene deletion strains for altered DNA content by flow cytometry. This analysis revealed that most gene deletions that altered cell cycle progression did not change cell size. Our results highlight a strong requirement for ribosomal biogenesis and protein synthesis for initiation of cell division. We also identified numerous factors that have not been previously implicated in cell cycle control mechanisms. We found that CBS, which catalyzes the synthesis of cystathionine from serine and homocysteine, advances START in two ways: by promoting cell growth, which requires CBS's catalytic activity, and by a separate function, which does not require CBS's catalytic activity. CBS defects cause disease in humans, and in animals CBS has vital, non-catalytic, unknown roles. Hence, our results may be relevant for human biology. Taken together, these findings significantly expand the range of factors required for the timely initiation of cell division. The systematic identification of non-essential regulators of cell division we describe will be a valuable resource for analysis of cell cycle progression in yeast and other organisms.


[A role of aryl hydrocarbon hydroxylase inducibility in susceptibility to lung carcinogenesis].
Lung cancer mortality has been increasing rapidly in recent years in Japan and is expected to exceed that of stomach cancer in male Japanese in the near future. Although chronic inhalation of cigarette smoke is a major risk factor for the development of lung cancer, it seems important to examine genetic susceptibility to the disease as well. Aryl hydrocarbon hydroxylase (AHH), a drug-metabolism enzyme, is useful in determining the individual differences in genetic susceptibility to lung carcinogenesis. AHH is a microsomal membrane-bound monooxygenase system located in most tissues of the body. In mice, AHH inducibility is under the control of the Ah locus and certain inbred strains of mice are susceptible to AHH induction by 3-methylcholanthrene treatment (Ah responsive strains), while other strains are not (Ah non-responsive strains). A strong correlation was observed between AHH inducibility and tumor incidence in mice. Since AHH is also responsible for the activation to carcinogens of benzo (a)pyrene and other aromatic hydrocarbons in cigarette smoke, it may also be important in humans in the causation of lung cancer. Kellermann et al. investigated the genetics of AHH in a human population and reported that the inducibility of this enzyme was controlled by a single gene locus with 2 dominant alleles. They classified humans as having low, intermediate, or high inducibility of AHH. In addition, they reported a significant positive correlation between the extent of inducibility and susceptibility to lung cancer. Their claim, however, has been both supported and refuted by subsequent investigators. Recently, a close association between development of lung cancer and three polymorphisms of CYP1A1 caused by the presence or absence of one MspI site in the 3'-flanking region, namely, a predominant homozygote pattern (A), a heterozygote pattern (B) and a homozygous rare allele pattern (C), has been reported. The relationship between AHH inducibility and polymorphisms of CYP1A1 had not been investigated previously. Our study indicated that the genotype of C, very frequent in Kreyberg type I, was closely related to high AHH inducibility. Thus, the relationship between AHH inducibility and lung cancer, suggested by Kellermann et al., is supported by our study. Further studies will be needed to confirm the present results. Identification of smokers who have genetically high susceptibility to lung cancer (pattern C), may become important for the prevention of lung cancer.


The future and promise of cognitive behavioral therapy: a commentary.
The Academy for Psychological Clinical Science and the independent accrediting entity it created, the Psychological Clinical Science Accreditation system, have recently launched a movement aimed at reforming all of clinical psychology. If this movement is successful, it will result in a greater emphasis on empirical science in the practice of clinical psychology. As cognitive behavioral therapy (CBT) is the approach that currently has the greatest number of controlled scientific studies supporting it, this should be an impetus for CBT to grow. The very same scientific evidence that supports the efficacy of CBT, however, also shows that CBT is far from fully efficacious. Several recent trends that hold great promise to enhance the effectiveness of CBT are discussed, such as greater integration of CBT with biological approaches, cognitive science, systemic approaches, motivational interviewing, and strengths-based approaches.


Mammary epithelial cell and adipocyte co-culture in a 3-D matrix: the first step towards tissue-engineered human breast tissue.
Reconstruction of the female breast after cancer surgery is a demanding task where the methods used today suffer from several disadvantages. In the present study we have investigated the possibility to use tissue engineering methods to regenerate human autologous breast tissue. Human mammary epithelial cells and preadipocytes were derived from breast tissue biopsies from healthy women undergoing reduction mammoplasty, and the two celltypes were co-cultured with conventional cell culture methods as well as in 3-D matrices. The study shows that it is possible to harvest both human mammary epithelial cells and preadipocytes in a single session, propagate several subcultures, and that the cells maintain a normal intercellular distribution and growth-pattern when co-cultured in a 3-D collagen gel. We propose that growth and formation of a tissue closely resembling normal human breast tissue be readily obtained in the described in vitro cell culture set-up using basic tissue engineering principles. This concept may be of great importance in the development of new methods for reconstruction of the human breast.


Mild iridium-catalyzed borylation of arenes. High turnover numbers, room temperature reactions, and isolation of a potential intermediate.
The borylation of arenes leads to the formation of synthetically versatile products from unactivated arene reagents. We report that Ir(I) precursors in conjunction with bipyridine ligands catalyze in high yields the borylation of arenes under mild conditions. These reactions encompase arenes bearing both electron-withdrawing and electron-donating substituents. The temperatures required for the transformation are much lower than those previously reported for direct arene borylation. The combination of [Ir(COE)2Cl]2 and (4,4-di-t-butyl)bipyridine even allows for reaction at room temperature. The same catalyst system at 100 degrees C provides remarkably high turnover numbers for a hydrocarbon functionalization process. Mechanistic studies show that the reactions involve uncommon, Ir(II) tris-boryl complexes. An example of this type of complex ligated by di-t-butylbipyridine was isolated and structurally characterized. It reacted rapidly at room temperature to produce aryl boronate esters in high yields.


Time perspective, control, and affect mediate the relation between regulatory mode and procrastination.
This study examines the roles of time perspective, affect, and locus of control in mediating the relationship between regulatory mode and procrastination. Participants filled out the Zimbardo Time Perspective Inventory, Positive and Negative Affect Schedule Scale, Multidimensional Locus of Control Inventory, Locomotion and Assessment Scale, and Lay's General Procrastination scale. Results showed that procrastination was negatively related to locomotion orientation but positively associated with assessment orientation. The relations between regulatory mode and procrastination were mediated by negative affective state, internal sense of control, and negative past and future time perspectives. These findings suggest not only a behavioral link between regulatory mode and procrastination but also affective and cognitive differences in locomotion and assessment orientations that may account for such linkage. The present results also provide empirical support for the theory of locomotion-temporality interface (Kruglanski, Pierro, & Higgins, 2016).


Negative responses to urban residential noise as a social rebound effect of increasing population density: Legislative challenges and auditory territoriality.
Populations in cities are projected to increase globally, densifying urban residential environments with both positive and negative effects. Positive social effects are offset by negative health effects however; urban residential noise has been identified in a large number of studies as a significant contributor to social unrest as well as a risk to physiological and psychological health caused by stress, making this topic highly relevant to the discussion on sustainability urban growth. Focusing on the psychological rebound effect of urban residential noise, this paper attempts to explain how and why auditory aspects of the spatial environment negatively influences urban residents. To provide context and to indicate areas in need of improvement, the legislative challenges to be faced are considered, with Sweden as a prime example of a first world country grappling with the effects of increased urban density. Existing building legislation regarding residential noise is considered in relation to studies investigating the effects of residential noise on psychological and physiological health, outlining areas in need of future development. Then, health responses to residential noise are placed in a broader evolutionary context by considering how these effects might be the result of triggered evolutionary mechanisms for keeping population size optimal. Further, the spatial dimension of hearing is discussed with reference to theories of territoriality in environmental psychology and the concept of auditory territoriality is described.


Extra-articular manifestations and burden of disease in patients with radiographic and non-radiographic axial spondyloarthritis.
Although the prevalence of peripheral and extra-articular disease in ankylosing spondylitis (AS) has been assessed in many studies, data on non-radiographic axial spondyloarthritis (nr-axSpA) is scanty. The aim of this study was first, to compare radiographic-axSpA/AS (r-axSpA/AS) and nr-axSpA concerning peripheral arthritis and extra-articular manifestations (EAMs), and second, to assess potential differences between patient subgroups with or without EAMs regarding disease burden. Data was extracted from our single center axSpA database. Patients having at least one of the EAMs (uveitis and/or inflammatory bowel disease (IBD) and/or psoriasis) were compared to those who did not have EAMs. Patients' clinical data including disease activity, functional and psychological status, physical limitations, quality of life (QoL) and magnetic resonance imaging of sacroiliac joints (SIJ MR) were evaluated. Patients with nr-axSpA (n=193) were younger, had female predominance, better functional and physical status, higher frequency of bone edema in SIJ MR and peripheral arthritis but similar QoL, prevalence of HLA B27 and EAMs compared to r-axSpA/AS (n=352). The prevalence of current or ever uveitis (14.5 vs 15.3%, p=0.791), psoriasis (6.2 vs 5.4%, p=0.689) or IBD (4.1 vs 3.4%, p=0.663) in nr-axSpA and r-axSpA/AS were similar. In both subgroup of patients, EAMs positive and negative patients had similar functional status and QoL, as well as disease activity and laboratory parameters. Patients with nr-axSpA and r-axSpA/AS have similar prevalence of EAMs and clinical burden of disease. Having EAMs does not have a major influence on clinical parameters and patient reported outcome measures in nr-axSpA and r-axSpA/AS.


Genome-wide evidence of Austronesian-Bantu admixture and cultural reversion in a hunter-gatherer group of Madagascar.
Linguistic and cultural evidence suggest that Madagascar was the final point of two major dispersals of Austronesian- and Bantu-speaking populations. Today, the Mikea are described as the last-known Malagasy population reported to be still practicing a hunter-gatherer lifestyle. It is unclear, however, whether the Mikea descend from a remnant population that existed before the arrival of Austronesian and Bantu agriculturalists or whether it is only their lifestyle that separates them from the other contemporary populations of South Madagascar. To address these questions we have performed a genome-wide analysis of >700,000 SNP markers on 21 Mikea, 24 Vezo, and 24 Temoro individuals, together with 50 individuals from Bajo and Lebbo populations from Indonesia. Our analyses of these data in the context of data available from other Southeast Asian and African populations reveal that all three Malagasy populations are derived from the same admixture event involving Austronesian and Bantu sources. In contrast to the fact that most of the vocabulary of the Malagasy speakers is derived from the Barito group of the Austronesian language family, we observe that only one-third of their genetic ancestry is related to the populations of the Java-Kalimantan-Sulawesi area. Because no additional ancestry components distinctive for the Mikea were found, it is likely that they have adopted their hunter-gatherer way of life through cultural reversion, and selection signals suggest a genetic adaptation to their new lifestyle.


Preferential Growth of Semiconducting Single-Walled Carbon Nanotubes on Substrate by Europium Oxide.
In this paper, we have demonstrated that europium oxide (Eu(2)O(3)) is a new type of active catalyst for single-walled carbon nanotubes (SWNTs) growth under suitable conditions. Both random SWNT networks and horizontally aligned SWNT arrays are efficiently grown on silicon wafers. The density of the SWNT arrays can be altered by the CVD conditions. This result further provides the experimental evidence that the efficient catalyst for SWNT growth is more size dependent than the catalysts themselves. Furthermore, the SWNTs from europium sesquioxides have compatibly higher quality than that from Fe/Mo catalyst. More importantly, over 80% of the nanotubes from Eu(2)O(3) are semiconducting SWNTs (s-SWNTs), indicating the preferential growth of s-SWNTs from Eu(2)O(3). This new finding could open a way for selective growth of s-SWNTs, which can be used as high-current nanoFETs and sensors. Moreover, the successful growth of SWNTs by Eu(2)O(3) catalyst provides new experimental information for understanding the preferential growth of s-SWNTs from Eu(2)O(3), which may be helpful for their controllable synthesis.


Association between breakfast frequency and physical activity and sedentary time: a cross-sectional study in children from 12 countries.
Existing research has documented inconsistent findings for the associations among breakfast frequency, physical activity (PA), and sedentary time in children. The primary aim of this study was to examine the associations among breakfast frequency and objectively-measured PA and sedentary time in a sample of children from 12 countries representing a wide range of human development, economic development and inequality. The secondary aim was to examine interactions of these associations between study sites. This multinational, cross-sectional study included 6228 children aged 9-11 years from the 12 International Study of Childhood Obesity, Lifestyle and the Environment sites. Multilevel statistical models were used to examine associations between self-reported habitual breakfast frequency defined using three categories (breakfast consumed 0 to 2 days/week [rare], 3 to 5 days/week [occasional] or 6 to 7 days/week [frequent]) or two categories (breakfast consumed less than daily or daily) and accelerometry-derived PA and sedentary time during the morning (wake time to 1200 h) and afternoon (1200 h to bed time) with study site included as an interaction term. Model covariates included age, sex, highest parental education, body mass index z-score, and accelerometer waking wear time. Participants averaged 60 (s.d. 25) min/day in moderate-to-vigorous PA (MVPA), 315 (s.d. 53) min/day in light PA and 513 (s.d. 69) min/day sedentary. Controlling for covariates, breakfast frequency was not significantly associated with total daily or afternoon PA and sedentary time. For the morning, frequent breakfast consumption was associated with a higher proportion of time in MVPA (0.3%), higher proportion of time in light PA (1.0%) and lower min/day and proportion of time sedentary (3.4 min/day and 1.3%) than rare breakfast consumption (all p ≤ 0.05). No significant associations were found when comparing occasional with rare or frequent breakfast consumption, or daily with less than daily breakfast consumption. Very few significant interactions with study site were found. In this multinational sample of children, frequent breakfast consumption was associated with higher MVPA and light PA time and lower sedentary time in the morning when compared with rare breakfast consumption, although the small magnitude of the associations may lack clinical relevance. The International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) is registered at (Identifier NCT01722500 ).


Physio-Biochemical Responses of Sweet Cherry Leaf to Natural Cold Conditions.
Trees of the sweet cherry cultivar 'Grace Star' (Prunus avium L.) were exposed to low temperatures without frost for two consecutive nights under natural conditions 36 d after flowering, to study the effects on the physiological properties and metabolic status of leaves. The response was studied by measuring chlorophyll fluorescence and gas exchange parameters and by analyzing chloroplast pigments (i) immediately after exposure, (ii) 24 h and (iii) 48 h later. The first exposure at 2.4 (±0.2) °C and a minimum of 0.8 °C elicited more changes than the second exposure at 4.9 (±0.3) °C and a minimum of 2.4 °C. After the first exposure, the maximum quantum yield of PS II (Fv/Fm), effective quantum efficiency of PS II, net photosynthesis (PN), stomatal conductance (gs), transpiration, and intercellular CO2 concentration were significantly lower, and after the second exposure, the content of chlorophyll b, total chlorophyll, β-carotene, and lutein were lower. The content of antheraxanthin and zeaxanthin was higher immediately after both exposures, and that of antheraxanthin was also higher 24 h later. Recovery took longer in trees that were exposed twice. Fv/Fm recovered within 48 h, but the de-epoxidation state of the xanthophyll cycle pool, PN, and gs did not reach the level of controls, indicating that the stress effect lasted several days which is probably sufficient to cause fruit drop and reduce yield.


Nanoparticulate drug delivery systems for the treatment of neglected tropical protozoan diseases.
Neglected Tropical Diseases (NTDs) comprise of a group of seventeen infectious conditions endemic in many developing countries. Among these diseases are three of protozoan origin, namely leishmaniasis, Chagas disease, and African trypanosomiasis, caused by the parasites Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei respectively. These diseases have their own unique challenges which are associated with the development of effective prevention and treatment methods. Collectively, these parasitic diseases cause more deaths worldwide than all other NTDs combined. Moreover, many current therapies for these diseases are limited in their efficacy, possessing harmful or potentially fatal side effects at therapeutic doses. It is therefore imperative that new treatment strategies for these parasitic diseases are developed. Nanoparticulate drug delivery systems have emerged as a promising area of research in the therapy and prevention of NTDs. These delivery systems provide novel mechanisms for targeted drug delivery within the host, maximizing therapeutic effects while minimizing systemic side effects. Currently approved drugs may also be repackaged using these delivery systems, allowing for their potential use in NTDs of protozoan origin. Current research on these novel delivery systems has provided insight into possible indications, with evidence demonstrating their improved ability to specifically target pathogens, penetrate barriers within the host, and reduce toxicity with lower dose regimens. In this review, we will examine current research on these delivery systems, focusing on applications in the treatment of leishmaniasis, Chagas disease, and African trypanosomiasis. Nanoparticulate systems present a unique therapeutic alternative through the repositioning of existing medications and directed drug delivery.


Detecting repeated cancer evolution from multi-region tumor sequencing data.
Recurrent successions of genomic changes, both within and between patients, reflect repeated evolutionary processes that are valuable for the anticipation of cancer progression. Multi-region sequencing allows the temporal order of some genomic changes in a tumor to be inferred, but the robust identification of repeated evolution across patients remains a challenge. We developed a machine-learning method based on transfer learning that allowed us to overcome the stochastic effects of cancer evolution and noise in data and identified hidden evolutionary patterns in cancer cohorts. When applied to multi-region sequencing datasets from lung, breast, renal, and colorectal cancer (768 samples from 178 patients), our method detected repeated evolutionary trajectories in subgroups of patients, which were reproduced in single-sample cohorts (n = 2,935). Our method provides a means of classifying patients on the basis of how their tumor evolved, with implications for the anticipation of disease progression.


Characteristics of responders and non-responders to risperidone monotherapy or placebo in co-occurring bipolar disorder and anxiety disorder.
Clinical characteristics predicting response and remission to psychopharmacological treatment of bipolar disorder (BD) and co-occurring anxiety disorders have been understudied. We hypothesized that non-response to risperidone or placebo in individuals with co-occurring BD and anxiety symptoms would be associated with a more severe clinical course of BD, and certain demographic variables. This study was a secondary analysis of a randomized, double-blind, parallel, 8-week study comparing risperidone monotherapy and placebo in individuals with BD plus current panic disorder, current generalized anxiety disorder (GAD), or lifetime panic disorder (n=111) [31]. We compared clinical characteristics of responders (50% improvement on the Hamilton Anxiety Scale [HAM-A]) and non-responders as well as remitters (HAM-A<7) and non-remitters in risperidone treatment (n=54) and placebo (n=57) groups. For non-responders in the risperidone group, co-occurring lifetime panic disorder was significantly more common than for non-responders in the placebo group. Apart from this, no significant differences in course of illness or demographics were found either between or across groups for patients with BD and co-occurring anxiety symptoms receiving risperidone or placebo in this acute phase study.


Structure and conformational change of a replication protein A heterotrimer bound to ssDNA.
Replication protein A (RPA) is the main eukaryotic ssDNA-binding protein with essential roles in DNA replication, recombination, and repair. RPA maintains the DNA as single-stranded and also interacts with other DNA-processing proteins, coordinating their assembly and disassembly on DNA. RPA binds to ssDNA in two conformational states with opposing affinities for DNA and proteins. The RPA-protein interactions are compatible with a low DNA affinity state that involves DNA-binding domain A (DBD-A) and DBD-B but not with the high DNA affinity state that additionally engages DBD-C and DBD-D. The structure of the high-affinity RPA-ssDNA complex reported here shows a compact quaternary structure held together by a four-way interface between DBD-B, DBD-C, the intervening linker (BC linker), and ssDNA. The BC linker binds into the DNA-binding groove of DBD-B, mimicking DNA. The associated conformational change and partial occlusion of the DBD-A-DBA-B protein-protein interaction site establish a mechanism for the allosteric coupling of RPA-DNA and RPA-protein interactions.


First Trimester Screening for Fetal Aneuploidies Using Placental Growth Factor: The Great Obstetrical Syndrome (GOS) Study.
This study sought to estimate the ability of first trimester maternal serum placental growth factor (PlGF) to identify fetal aneuploidies. A prospective cohort study of singleton pregnancy at 11 to 13 weeks was conducted. Maternal serum PlGF concentration was measured using BRAHMS PlGF plus KRYPTOR automated assays (Thermo Scientific BRAHMS, Hennigsdorf, Germany). PlGF and nuchal translucency were log-transformed and reported as multiples of the median (MoM) adjusted for crown-rump length. Detection rates were calculated using receiver-operator characteristic curves. The study observed 21 cases of fetal aneuploidies (0.4%) out of 4765 participants. Trisomy 21 (13 cases; 0.85 MoM; interquartile range [IQR] 0.80-0.93), trisomy 18 (two cases; 0.77 MoM; IQR 0.66-0.87) and trisomy 13 (two cases; 0.68 MoM; IQR 0.61-0.75) were associated with low PlGF concentrations. The low PlGF values observed in the cases of monosomy X (two cases; 0.85 MoM; IQR 0.82-0.88, P = 0.05), triploidy (0.78 MoM, P = 0.11), and 47,XX,i(22)(p10) (0.18 MoM, P = 0.08) were not statistically different from the controls. A model including maternal age, nuchal translucency, and PlGF could have identified all (95% CI 83%-100%) cases of trisomy 21 and six of the other fetal aneuploidies (75%) at a false-positive rate of 9%. Low first trimester PlGF is associated with an increased risk of fetal aneuploidy. PlGF combined with first trimester ultrasound (nuchal translucency, uterine artery Doppler, and early fetal anatomy) could identify not only women at high risk for preeclampsia, but also fetuses at high risk of aneuploidy for optimal further testing (non-invasive testing for common aneuploidy screening or chorionic villus sampling for full screening and diagnosis).


Metabolism in anoxic permeable sediments is dominated by eukaryotic dark fermentation.
Permeable sediments are common across continental shelves and are critical contributors to marine biogeochemical cycling. Organic matter in permeable sediments is dominated by microalgae, which as eukaryotes have different anaerobic metabolic pathways to prokaryotes such as bacteria and archaea. Here we present analyses of flow-through reactor experiments showing that dissolved inorganic carbon is produced predominantly as a result of anaerobic eukaryotic metabolic activity. In our experiments, anaerobic production of dissolved inorganic carbon was consistently accompanied by large dissolved H2 production rates, suggesting the presence of fermentation. The production of both dissolved inorganic carbon and H2 persisted following administration of broad spectrum bactericidal antibiotics, but ceased following treatment with metronidazole. Metronidazole inhibits the ferredoxin/hydrogenase pathway of fermentative eukaryotic H2 production, suggesting that pathway as the source of H2 and dissolved inorganic carbon production. Metabolomic analysis showed large increases in lipid production at the onset of anoxia, consistent with documented pathways of anoxic dark fermentation in microalgae. Cell counts revealed a predominance of microalgae in the sediments. H2 production was observed in dark anoxic cultures of diatoms (Fragilariopsis sp.) and a chlorophyte (Pyramimonas) isolated from the study site, substantiating the hypothesis that microalgae undertake fermentation. We conclude that microalgal dark fermentation could be an important energy-conserving pathway in permeable sediments.


Dieting practices, weight perceptions, and body composition: a comparison of normal weight, overweight, and obese college females.
Of concern to health educators is the suggestion that college females practice diet and health behaviors that contradict the 2005 dietary guidelines for Americans. In this regard, there remain gaps in the research related to dieting among college females. Namely, do normal weight individuals diet differently from those who are overweight or obese, and are there dieting practices used by females that can be adapted to promote a healthy body weight? Since it is well recognized that females diet, this study seeks to determine the dieting practices used among normal, overweight, and obese college females (do they diet differently) and identify dieting practices that could be pursued to help these females more appropriately achieve and maintain a healthy body weight. A total of 185 female college students aged 18 to 24 years participated in this study. Height, weight, waist and hip circumferences, and skinfold thickness were measured to assess body composition. Surveys included a dieting practices questionnaire and a 30-day physical activity recall. Participants were classified according to body mass index (BMI) as normal weight (n = 113), overweight (n = 35), or obese (n = 21). Data were analyzed using JMP IN(R) software. Descriptive statistics included means, standard deviations, and frequency. Subsequent data analysis involved Pearson X2 and one-way analysis of variance with comparison for all pairs that were significantly different using Tukey-Kramer honestly significant difference test. Outcomes of this study indicate the majority of participants (83%) used dieting for weight loss and believed they would be 2% to 6% greater than current weight if they did not diet; normal weight, overweight, and obese groups perceived attractive weight to be 94%, 85%, and 74%, respectively, of current weight; 80% of participants reported using physical activity to control weight, although only 19% exercised at a level that would promote weight loss; only two of 15 dieting behaviors assessed differed in terms of prevalence of use among groups, which were consciously eating less than you want (44% normal weight, 57% overweight, 81% obese) and using artificial sweeteners (31% normal weight and overweight, 5% obese); and the most prevalent explicit maladaptive weight loss behavior was smoking cigarettes (used by 9% of participants) and most unhealthy was skipping breakfast (32%). Collectively, results indicate female college students, regardless of weight status, would benefit from open discussions with health educators regarding healthy and effective dieting practices to achieve/maintain a healthy body weight. The results are subject to replication among high school, middle-aged, and older females.