Large-scale delivery of seasonal malaria chemoprevention to children under 10 in Senegal: an economic analysis.
Seasonal Malaria Chemoprevention (SMC) is recommended for children under 5 in the Sahel and sub-Sahel. The burden in older children may justify extending the age range, as has been done effectively in Senegal. We examine costs of door-to-door SMC delivery to children up to 10 years by community health workers (CHWs). We analysed incremental financial and economic costs at district level and below from a health service perspective. We examined project accounts and prospectively collected data from 405 CHWs, 46 health posts, and 4 district headquarters by introducing questionnaires in advance and completing them after each monthly implementation round. Affordability was explored by comparing financial costs of SMC to relevant existing health expenditure levels. Costs were disaggregated by administration month and by health service level. We used linear regression models to identify factors associated with cost variation between health posts. The financial cost to administer SMC to 180 000 children over one malaria season, reaching ∼93% of children with all three intended courses of SMC was $234 549 (constant 2010 USD) or $0.50 per monthly course administered. Excluding research-participation incentives, the financial cost was $0.32 per resident (all ages) in the catchment area, which is 1.2% of Senegal's general government expenditure on health per capita. Economic costs were 18.7% higher than financial costs at $278 922 or $0.59 per course administered and varied widely between health posts, from $0.38 to $2.74 per course administered. Substantial economies of scale across health posts were found, with the smallest health posts incurring highest average costs per monthly course administered. SMC for children up to 10 is likely to be affordable, particularly where it averts substantial curative care costs. Estimates of likely costs and cost-effectiveness of SMC in other contexts must account for variation in average costs across delivery months and health posts.


Surface Propensity of Atmospherically Relevant Amino Acids Studied by XPS.
Amino acids constitute an important fraction of the water-soluble organic nitrogen (WSON) compounds in aerosols and are involved in many processes in the atmosphere. In this work, we applied X-ray photoelectron spectroscopy (XPS) to study aqueous solutions of four amino acids, glycine, alanine, valine, and methionine, in their zwitterionic forms. We found that amino acids with hydrophilic side chains and smaller size, GLY and ALA, tend to stay in the bulk of the liquid, while the hydrophobic and bigger amino acids, VAL and MET, are found to concentrate more on the surface. We found experimental evidence that the amino acids have preferential orientation relative to the surface, with the hydrophobic side chain being closer to the surface than the hydrophilic carboxylate group. The observed amino acid surface propensity has implications in atmospheric science as the surface interactions play a central role in cloud droplet formation, and they should be considered in climate models.


Duodenal pseudomelanosis (pseudomelanosis duodeni): a rare endoscopic finding.
Duodenal pseudomelanosis (or pseudomelanosis duodeni) is a rare benign condition characterized by black-brown speckled pigmentation of the duodenal mucosa. Collections of pigment-laden macrophages are found in the tips of duodenal villi. The pigment is thought to be mostly composed of ferrous sulfide. Histochemichal stains for iron (Perl's prussian blue) or melanin (Masson-Fontana) may be positive, but are usually negative or unpredictable. Duodenal pseudomelanosis occurs predominantly in middle-aged to old adults and more commonly in females. It is associated with chronic renal failure, arterial hypertension, diabetes mellitus and gastrointestinal bleeding. Medications such as ferrous sulfate, hydralazine, propranolol, hydrochlorothiazide and furosemide are thought to play a role as well. We report a case of a 86-year-old female who presented with a history of watery diarrhea and melena. The patient had a history of high blood pressure and ischemic stroke episodes. She was on multiple medication including hidralazine, captopril, hydrochlorthiazide and aspirin. She was dehydrated, her blood pressure was 96 × 60 mmHg and neurologic examination showed complete left hemiplegia with central VII nerve palsy. Laboratory tests showed normal serum electrolytes and renal function. Hemoglobin level was 10.7 g%. An upper endoscopy showed multiple diminutive black spots throughout the distal duodenal bulb and second portion. Histology showed multiple foci of a brown-black granular pigment inside macrophages within the tips of the villi (pseudomelanosis). Stains for iron and melanin were negative. She was treated with omeprazol, parenteral fluid replacement with saline and partial fasting. After complete recovery she was discharged for ambulatory follow up.


Isolated Renal Artery Dissection: A Systematic Review of Case Reports.
Isolated renal artery dissection (IRAD) is a rare and often unrecognized clinical entity, with a paucity of data on its epidemiology and management. We extracted 129 cases of IRAD from the medical literature between 1972 and 2016. IRAD as a result of an extended dissection from the aorta and splanchnic or mesenteric arteries was excluded. The mean age of presentation was 42.7±12.9 years, with a male predominance (79%). Abdominal pain (75.9%) was the most common presenting symptom. Etiology was more likely to be spontaneous (76%) than traumatic (12%), iatrogenic (9%), or drug-induced (1.5%). The most common risk factors were hypertension (28.7%), fibromuscular dysplasia (8.5%), and Ehlers-Danlos syndrome (5.4%). Unilateral renal artery dissection (right 45.5%, left 40.5%) was more frequent than bilateral (14%). More than half (56.6%) of the cohort were managed medically (blood pressure control and /or anticoagulation). Of those who underwent intervention, endovascular stenting or embolization (35%) was utilized more frequently than nephrectomy or bypass (21%). Computed tomography (CT) and magnetic resonance angiography (MRA) have the highest diagnostic sensitivity (91% and 93%, respectively) as compared to ultrasonography (27%). A high degree of clinical suspicion is required to diagnose IRAD. CT and MRI have a higher diagnostic sensitivity. As compared to invasive management, conservative management has comparable outcomes.


A novel intergenic variant, rs2004339 A/G, of the gene encoding interleukin-40, C17orf99, is associated with risk of rheumatoid arthritis in Iraqi women.
Interleukin-40 (IL-40) is a novel cytokine encoded by the chromosome 17 open reading frame 99 (C17orf99) gene. Recent studies have shown that IL-40 levels are significantly up-regulated in patients with rheumatoid arthritis (RA). However, the association of genetic variants of the C17orf99 gene with the risk of RA has not been investigated. In this case-control study, two intergenic variants, rs2004339 A/G and rs2310998 G/A, were genotyped for the first time in 120 Iraqi women with RA (30 newly diagnosed [ND] and 90 medicated [MD; treated with the tumor necrosis inhibitor etanercept plus methotrexate]) and 110 control women using TaqMan 5'-allele discrimination method. Serum IL-40 levels were also determined using an enzyme-linked immunosorbent assay kit. Multinomial logistic regression analysis was used to analyze rs2004339 and rs2310998 under five genetic models (allele, recessive, dominant, over-dominant, and co-dominant). Results revealed that the mutant A allele (allele model) and the homozygous AA genotype (co-dominant model) of rs2004339 were significantly associated with an increased risk of RA (odds ratio [OR] = 3.37 and 7.44, respectively; corrected probability [pc] < 0.001), while rs2310998 showed no association with RA risk. When comparing the allele and genotype frequencies of rs2004339 and rs2310998 between ND and MD patients, there were no statistically significant differences. Haplotype analysis of the two variants (in the order rs2004339-rs2310998) revealed that haplotypes A-A (OR = 1.72; pc = 0.024) and A-G (OR = 2.85; pc < 0.001) were associated with an increased risk of RA. IL-40 levels (median and interquartile range) were significantly elevated in RA patients compared to controls (29.3 [15.5-41.5] vs. 12.6 [7.4-18.8] pg/mL; p < 0.001). IL-40 levels were not influence by disease duration or disease activity, but the rs2310998 genotypes had an effect; IL-40 levels were significantly higher in women with the AA genotype than in women with the GG genotype (20.1 [12.9-37.1] vs. 15.8 [8.3-22.6] pg/mL; p = 0.006). Regarding medication, IL-40 tended to show elevated levels in ND cases compared to MD cases but without a significant difference. In conclusion, the mutant A allele and the mutant-type AA genotype of the intergenic variant rs2004339 were associated with an increased risk of RA among Iraqi women. Serum IL-40 levels were also elevated in patients, particularly ND patients, and were positively affected by the mutant-type AA genotype. Accordingly, the role of IL-40 in the pathogenesis of RA has been indicated.


Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol.
Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.


Involvement of macrophage chemotactic protein-1 and interleukin-1beta during inflammatory but not basic fibroblast growth factor-dependent neovascularization in the mouse cornea.
Corneal neovascularization develops in several pathologic conditions, but its underlying mechanisms remain elusive. We used a mouse inflammatory corneal model (corneas cauterized with silver nitrate) and assessed the role of monocyte/macrophage-attracting factors, macrophage chemotactic protein-1 (MCP-1), and a proinflammatory cytokine, IL-1beta, on macrophage recruitment and neovascularization. Both MCP-1, IL-1beta protein, and mRNA levels increased markedly 12 hours after the chemical cauterization. In situ hybridization showed that MCP-1 was located in corneal epithelial cells, and IL-1beta was located in corneal epithelial cells and infiltrating inflammatory cells. In addition, double staining of corneas with antibodies specific for monocytes/macrophages and IL-1beta revealed that IL-1beta was found in infiltrating monocytes/macrophages at Day 2 after cauterization. Both IL-1beta and MCP-1 induced neovascularization in a rat cornea model, and the cauterization-induced corneal neovascularization was partially inhibited by subconjunctival injection of anti-IL-1beta or anti-MCP-1. Coadministration of two antibodies inhibited corneal neovascularization slightly more than that by the administration of each. In contrast, administration of the anti-MCP-1 or anti-IL-1beta showed minimal inhibition of basic fibroblast growth factor-driven corneal neovascularization by mouse cornea assay. Cauterized corneas treated with anti-MCP-1 antibody had significantly fewer monocytes/macrophages than control. These results indicate the existence of distinct monocyte/macrophage-involved angiogenic pathways in mouse cornea, in which MCP-1 released from corneal epithelial cells attracts monocytes/macrophages into the cornea, where they release IL-1beta leading to inflammatory neovascularization. In addition, the IL-1beta and MCP-1 released from the corneal epithelial cells may directly induce corneal neovascularization.


Gut decontamination prevents bronchoscopy-induced bacterial translocation. An experimental study in rats.
Selective gut decontamination is suggested to suppress the gram-negative bacterial overgrowth in the intestine and consequently to reduce bacterial translocation. The purpose of the present study is to examine the effects of gut decontamination on bronchoscopy-induced bacterial translocation, and intestinal mucosal injury. Forty-five rats were assigned into three groups. Group 1 served as control (n=15). Group 2 (n=15) and group 3 (n=15) underwent bronchoscopy. In addition, group 3 underwent gut decontamination. Gut decontamination was performed two days prior to bronchoscopy with erythromycin and neomycin. Twenty-four hours after bronchoscopy, blood, mesenteric lymph nodes, spleen, liver, ileum and cecum were harvested for bacterial determination. The ileum was also assessed and graded histologically according to Chiu's injury scale. In the bronchoscopy group, bacterial translocation to the mesenteric lymph nodes was found in 7/15 rats (46.7%), compared to none of the controls (p=0.01). These rats also showed significant evidence of intestinal injury, compared to the controls (mean ranks, 32.7 or 8.5, p<0.0001). On the other hand, gut decontamination prevented bacterial translocation, compared to the bronchoscopy group (p=0.011). However, gut decontamination provided no beneficial effect on the intestinal mucosal injury, compared to the bronchoscopy group. These animals also revealed significant intestinal injury, compared to the controls (mean ranks, 27.8 or 8.5, p<0.0001). Our data shows that despite no amelioration in bronchoscopy-induced intestinal mucosal injury, gut decontamination has a preventive role for bronchoscopy-induced bacterial translocation.


Pulmonary elastic recoil and diffusing capacity in subjects with intermediate concentrations of alpha-1 antitrypsin.
Serum from 224 males investigated in a prospective study of respiratory disorders in a recently established asbestos industry has been estimated for alpha-1 antitrypsin (AAT) concentration by single radial immunodiffusion. Mean AAT concentration was 213-4 mg/dl). No subject with a markedly reduced level was found. A comprehensive range of lung function tests sensitive to changes anticipated in emphysema at a preclinical stage, included measurements of diffusing capacity and pulmonary elastic recoil. The 26 subjects with AAT concentration less than 150 mg/dl, were regarded as likely to comprise a majority of genotypes MZ and SS, and the 19 subjects with AAT concentration greater than 300 mg/dl were considered to comprise mainly MM. No difference in pulmonary function could be demonstrated between these two groups. Evidence of diminished pulmonary elastic recoil was found in nine smoking subjects whose AAT concentrations were normal and also in one young non-smoking subject with moderately severe asthma, whose AAT concentration was 140 mg/dl. It is concluded that in a male working population, evidence of diminished pulmonary elastic recoil is not a function of AAT concentration.


Validity of a two-item screen for early psychosis.
Well-validated screening tools have been developed to identify people at high risk for psychosis, but these are rarely used outside of specialty clinics or research settings. The development of extremely brief and simple screening tools could increase dissemination, especially in settings with low buy-in such as those with low base rates of psychosis and/or time constraints. We sought to identify such a brief measure by modeling participant responses to three psychosis screening questionnaires (Prime Screen; Prodromal Questionnaire-Brief; Youth Psychosis At Risk Questionnaire) in a sample of 139 help-seeking individuals and 335 college students (age range: 12-25). Two screening questions with especially strong information characteristics were identified: "Do you see things that others can't or don't see?" and "Have you ever felt that someone was playing with your mind?" (Alternative two-item screens with similarly strong properties were also identified and validated using uncertainty quantified through Bayesian modeling.) The resulting measure was validated against clinician ratings of psychosis. The screen performed with a sensitivity of 53% and specificity 98% for clinically significant hallucinations or delusions, and sensitivity of 32% and specificity 99% for identifying people in an early phase of psychosis (clinical high risk or first episode psychosis).


Primary structure of a calcium channel that is highly expressed in the rat cerebellum.
Previous molecular cloning experiments showed that multiple isoforms of the alpha 1 subunit of voltage-gated Ca channels are expressed in the mammalian brain (designated rbA, rbB, rbC, and rbD). We report here the isolation and characterization of cDNAs encoding the rat brain class A (rbA) Ca channel. The rbA-126 cDNA encodes a 2212-amino acid protein that shares 33% sequence identity with the alpha 1 subunits of cardiac and skeletal muscle dihydropyridine-sensitive Ca channels. When compared with other Ca channels, the rbA channel is notably different in both the carboxyl terminus and in a large (474-amino acid) hydrophilic segment between domains II and III. Northern blot analysis shows that rbA transcripts are expressed in all regions of the rat central nervous system, but most prominently in the cerebellum. A more widespread distribution of rbA Ca channels is indicated by PCR analysis, which demonstrates the presence of class A transcripts in the rat heart and pituitary but not in the spleen, kidney, or liver. The rbA cDNA appears to encode a Ca channel alpha 1 subunit that is distinct from the dihydropyridine-sensitive Ca channel sequences and that is expressed in a variety of excitable cells.


[Polyamines in species of microorganisms of the intestinal group].
A study was made of polyamines (putrescine, spermidine and spermin) in various representatives of the Enterobacteriaceae family--E. coli, Sh, sonnei, Sh. flexneri and S. typhi abdominalis. All the strains under study contained putrescine and spermidine, and many Shigella and Salmonella strains had spermin in addition. There were significant differences in the quantitative content of polyamines in the individual species. By the ratio of nitrogen of polyamine to phosphorus of nucleic acid it is possible to assess the correlation in the content of polyamines and nucleic acids in the bacterial cells.


Clinical nurse specialist practice in evidence-informed multidisciplinary cardiac care.
Care gaps exist in the management of cardiac patients throughout the care continuum. The clinical nurse specialist (CNS) is paramount in the development, implementation, and evaluation of tools to assist care providers in the use of evidence-informed therapies to maximize patient outcomes. The purpose of this article was to describe the CNS practice in terms of these evidence-informed initiatives for defined cardiac populations. Putting evidence into practice is one of the primary responsibilities for the CNS practice. Evidence-informed tools such as clinical pathways have been implemented throughout the healthcare region to reduce care gaps for the acute myocardial infarction and cardiac surgery populations. These tools equip care providers with a standards document, physician order sets, cardiac rehabilitation referral process, care guide, depression screening tool, and patient education material. By incorporating interventions known to reduce avoidable adverse events in the cardiac population into the clinical pathways, patient outcomes have been impacted. Ongoing evaluation of the evidence-informed tools through regular tracking of key indicators has enabled refinement of existing processes and care. It is the CNS practice that ensures not only patient care standards, but also daily routine care are underpinned by scientific evidence. Bridging research with clinical practice remains the stronghold for CNS practice.


Directional hippocampal-prefrontal interactions during working memory.
Working memory refers to a system that is essential for performing complex cognitive tasks such as reasoning, comprehension and learning. Evidence shows that hippocampus (HPC) and prefrontal cortex (PFC) play important roles in working memory. The HPC-PFC interaction via theta-band oscillatory synchronization is critical for successful execution of working memory. However, whether one brain region is leading or lagging relative to another is still unclear. Therefore, in the present study, we simultaneously recorded local field potentials (LFPs) from rat ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) and while the rats performed a Y-maze working memory task. We then applied instantaneous amplitudes cross-correlation method to calculate the time lag between PFC and vHPC to explore the functional dynamics of the HPC-PFC interaction. Our results showed a strong lead from vHPC to mPFC preceded an animal's correct choice during the working memory task. These findings suggest the vHPC-leading interaction contributes to the successful execution of working memory.


The impact of price and tobacco control policies on the demand for electronic nicotine delivery systems.
While much is known about the demand for conventional cigarettes, little is known about the determinants of demand for electronic nicotine delivery systems (ENDS or e-cigarettes). The goal of this study is to estimate the own and cross-price elasticity of demand for e-cigarettes and to examine the impact of cigarette prices and smoke-free policies on e-cigarette sales. Quarterly e-cigarette prices and sales and conventional cigarette prices from 2009 to 2012 were constructed from commercial retail store scanner data from 52 U.S. markets, for food, drug and mass stores, and from 25 markets, for convenience stores. Fixed-effects models were used to estimate the own and cross-price elasticity of demand for e-cigarettes and associations between e-cigarette sales and cigarette prices and smoke-free policies. Estimated own price elasticities for disposable e-cigarettes centred around -1.2, while those for reusable e-cigarettes were approximately -1.9. Disposable e-cigarette sales were higher in markets where reusable e-cigarette prices were higher and where less of the population was covered by a comprehensive smoke-free policy. There were no consistent and statistically significant relationships between cigarette prices and e-cigarette sales. E-cigarette sales are very responsive to own price changes. Disposable e-cigarettes appear to be substitutes for reusable e-cigarettes. Policies increasing e-cigarette retail prices, such as limiting rebates, discounts and coupons and imposing a tax on e-cigarettes, could potentially lead to significant reductions in e-cigarette sales. Differential tax policies based on product type could lead to substitution between different types of e-cigarettes.


A Population-Based Systematic Clinical Analysis With a Single-Center Case Series of Patients With Pulmonary Large Cell Neuroendocrine Carcinoma.
This study aims to conduct an updated systematic analysis of patients with pulmonary large cell neuroendocrine carcinoma (PLCNC) in recent decades, concerning incidence and mortality trends, demographics, treatments, survival and death causes. Patients who were diagnosed with PLCNC at the Peking Union Medical College Hospital (PUMCH) between 2000 to 2020 were retrospectively analyzed. The population-based Surveillance, Epidemiology, and End Results (SEER) database were also retrieved. Frequencies and average annual age-adjusted rates (AAR) of PLCNC patients were calculated and analyzed by Joint-point regression. Univariate and multivariate Cox regression were used for identifying prognostic factors. Predictive nomograms for overall survival (OS) and cancer-specific survival (CSS) were developed and then validated by calculating C-index values and drawing calibration curves. Survival curves were plotted using the Kaplan-Meier method and compared by log-rank test. Causes of death were also analyzed by time latency. A total of 56 PLCNC patients of the PUMCH cohort were included. Additionally, the PLCNC patients in the SEER database were also identified from different subsets. The AAR from 2001 to 2017 were 3.21 (95%CI: 3.12-3.30) per million. Its incidence and mortality rates in PLCNC patients increased at first but seemed to decline in recent years. Besides TNM stage and treatments, older age and male gender were independently associated with poorer survival, while marital status only affected CSS other than OS. The nomograms for OS and CSS presented great predictive ability and calibration performance. Surgery gave significantly more survival benefits to PLCNC patients, and chemotherapy might add survival benefits to stage II-IV. However, radiation therapy seemed to only improve stage III patients' survival. This study supported some previous studies in terms of incidence, survival, and treatment options. The mortality rates seemed to decline recently, after an earlier increase. Among PLCNC patients, most of the deaths occurred within the first five years, while other non-PLCNC diseases increased after that. Thus, careful management and follow-up of other comorbidities are of equal importance. Our study may partly solve the dilemma caused by PLCNC's rarity and inspire more insights in future researches.


Ecology and energetics of encephalization in hominid evolution.
Hominid evolution is marked by very significant increase in relative brain size. Because relative brain size has been linked to energetic requirements it is possible to look at the pattern of encephalization as a factor in the evolution of human foraging and dietary strategies. Major expansion of the brain is associated with Homo rather than the Hominidae as a whole, and the energetic costs are likely to have forced a prolongation of growth rates and secondary altriciality. It is calculated here that modern human infants have energetic requirements approximately 9% greater than similar size apes due to their large brains. Consideration of energetic costs of brain allow the prediction of growth rates in hominid taxa and an examination of the implications for life-history strategy and foraging behaviour.


LupusQoL-FR is valid to assess quality of life in patients with systemic lupus erythematosus.
To cross-culturally adapt the LupusQoL into French, to test its measurement properties and to further investigate its domain structure. The cultural adaptation process according to guidelines and pre-testing resulted in the LupusQoL-FR. SLE patients completed the LupusQoL-FR at baseline, 15 days, 3 months and 6 months. Validity was studied through content and construct validity (factorial and Rasch analysis for structural validity, Spearman's correlation and Mann-Whitney tests for external validity). Cronbach's α and intra-class correlation coefficients were computed for reliability. The standardized response mean was computed to evaluate responsiveness. In all, 182 patients, age 39.6 (10.6) years, mostly outpatients [mean SELENA-SLEDAI 2.6 (3.5)] were recruited. Factor analysis with eight imposed factors was very close to the original LupusQoL. A screeplot with parallel analysis showed that LupusQoL domains could be aggregated in two physical and mental scales. Both eight- and two-factor structures showed a good Rasch fit, internal consistency (Cronbach's α: 0.85-0.95), and test-retest reliability (intra-class correlation coefficient 0.79-0.95). External convergent (correlation with SF-36, r=0.59-0.78) and divergent validity (according to SELENA-SLEDAI) were also satisfactory. The LupusQoL-FR is valid to assess quality of life in SLE patients. A two-factor structure of physical and mental aggregated scales is a valid alternative to the original eight-domain structure.


Human eosinophils are activated by cysteine proteases and release inflammatory mediators.
Recent studies suggest that serine proteases are involved in various biological responses through activation of protease-activated receptors (PARs). However, the functions of other proteases, such as cysteine proteases, are poorly understood and need elucidation. We examined the effects of an authentic cysteine protease, papain, and a protease derived from the mite allergen, Der f 1, on functions of human eosinophils. Purified eosinophils were incubated with papain or Der f 1. Eosinophil activation was monitored by superoxide anion generation and by degranulation. Intracellular signaling pathways were investigated through use of pharmacologic approaches. We found that papain potently induces human eosinophils to degranulate and to produce superoxide anion. A cysteine protease inhibitor, E-64, abolished the stimulatory effects of papain, which suggests that the protease activity of papain is necessary to trigger eosinophil responses. The eosinophil's response to papain was enhanced by IL-5 and mediated by activation of the phosphatidylinositol 3-kinase/Akt pathway. Interestingly, whereas a serine protease, trypsin, activated eosinophils through PAR2, the effects of papain were not inhibited by an antibody to PAR2, which suggests another novel mechanism for the eosinophils' response to cysteine proteases. It is likely that these observations are clinically important, because eosinophils were activated by a natural cysteine protease allergen, Der f 1, and released granule proteins. Human eosinophils are probably equipped with machineries that recognize and respond to cysteine proteases, such as those found at allergic inflammation sites; the result is active release of proinflammatory mediators.


Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study).
Genome-wide scans in Icelandic, Australian/New Zealand and Finnish pedigrees have provided evidence for maternal susceptibility loci for pre-eclampsia on chromosome 2, although at different positions (Iceland: 2p13 and 2q23, Australia/New Zealand: 2p11-12 and 2q22, Finland: 2p25). In this project, a large population-based (n=65 000) nested case-control study was performed in Norway to further explore the association between positional candidate genes on chromosome 2q and pre-eclampsia, using single-nucleotide polymorphisms (SNPs). DNA samples from 1139 cases (women with one or more pre-eclamptic pregnancies) and 2269 controls (women with normal pregnancies) were genotyped using the Applied Biosystems SNPlex high-throughput genotyping assay. In total, 71 SNPs within positional candidate genes at 2q22-23 locus on chromosome 2 were genotyped in each individual. Genotype data were statistically analysed with the sequential oligogenic linkage analysis routines (SOLAR) computer package. Nominal evidence of association was found for six SNPs (rs1014064, rs17742134, rs1424941, rs2161983, rs3768687 and rs3764955) within the activin receptor type 2 gene (ACVR2A) (all P-values <0.05). The non-independence of statistical tests due to linkage disequilibrium between SNPs at a false discovery rate of 5% identifies our four best SNPs (rs1424941, rs1014064, rs2161983 and rs3768687) to remain statistically significant. The fact that populations with different ancestors (Iceland/Norway-Australia/New Zealand) demonstrate a common maternal pre-eclampsia susceptibility locus on chromosome 2q22-23, may suggest a general role of this locus, and possibly the ACVR2A gene, in pre-eclampsia pathogenesis.


Alveolar soft-part sarcoma in the sacrum: a case report and review of the literature.
Alveolar soft part sarcoma (ASPS) is a rare disease of the soft tissue. Although the disease is rare, it is refractory to chemotherapy and radiation. En bloc surgical resection offers the best chance of cure. In this article we report the case of a 28-year-old woman who presented with buttock and leg pain, bowel, bladder and gait impairment and a large mass in the sacrum. Following surgical excision, the lesion was proven to be ASPS. On pathology, the mass was TFE3 (transcription factor E3) positive, indicating the presence of the ASPL-TFE3 (novel gene-transcription factor) translocation. Following surgery, the patient had improvement in her pain and ambulation; however, she refused adjuvant therapy to pursue hospice care and succumbed to her disease 2 years after surgery. On a review of the literature, it was found that ASPS of the bone constitutes a rare and formidable subset of this disease. Further, metastases related to ASPS are common in the lungs, liver, brain, and lymph nodes. The degree of dissemination is a predictor of outcome, with 5-year survival of 81-88% in patients with local disease and only 20-46% in patients with metastatic disease at the time of presentation. Brain metastases at the time of presentation portend the worst prognosis.


Carbon nanotubes as molecular transporters for walled plant cells.
We have investigated the capability of single-walled carbon nanotubes (SWNTs) to penetrate the cell wall and cell membrane of intact plant cells. Confocal fluorescence images revealed the cellular uptake of both SWNT/fluorescein isothiocyanate and SWNT/DNA conjugates, demonstrating that SWNTs also hold great promise as nanotransporters for walled plant cells. Moreover, the result suggested that SWNTs could deliver different cargoes into different plant cell organelles.


M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.


Studying the clinical encounter with the Adaptive Leadership framework.
In this paper we discuss the concept of leadership as a personal capability, not contingent on one's position in a hierarchy. This type of leadership allows us to reframe both the care-giving and organizational roles of nurses and other front-line clinical staff. Little research has been done to explore what leadership means at the point of care, particularly in reference to the relationship between health care practitioners and patients and their family caregivers. The Adaptive Leadership framework, based on complexity science theory, provides a useful lens to explore practitioners' leadership behaviors at the point of care. This framework proposes that there are two broad categories of challenges that patients face: technical and adaptive. Whereas technical challenges are addressed with technical solutions that are delivered by practitioners, adaptive challenges require the patient (or family member) to adjust to a new situation and to do the work of adapting, learning, and behavior change. Adaptive leadership is the work that practitioners do to mobilize and support patients to do the adaptive work. The purpose of this paper is to describe this framework and demonstrate its application to nursing research. We demonstrate the framework's utility with five exemplars of nursing research problems that range from the individual to the system levels. The framework has the potential to guide researchers to ask new questions and to gain new insights into how practitioners interact with patients at the point of care to increase the patient's ability to tackle challenging problems and improve their own health care outcomes. It is a potentially powerful framework for developing and testing a new generation of interventions to address complex issues by harnessing and learning about the adaptive capabilities of patients within their life contexts.


Cancer patients hospitalised for palliative reasons. Symptoms and needs presented at a university hospital.
The aim of this study was to identify patients in need of palliative care in 11 different care units with a total of 256 beds at Linköping University Hospital and to look at their overall situation with respect to assessed symptom control and quality of life. There were 46 patients fulfilling the two criteria of incurable cancer and need for palliative care, and each was assessed with the aid of a questionnaire (five oral questions on life situation) and a single visual analogue scale (VAS) about their overall quality of life (QoL). Each patient also assessed him- or herself on the Edmonton Symptom Assessment Scale (ESAS). Total ESAS scores ranged from 20 to 639 mm (median 211). Median VAS scores (100 mm = greatest symptom severity) were as follows: nausea 6 mm, pain 9 mm, anxiety 17 mm, depression 18 mm, drowsiness 35 mm, activity 38 mm, appetite 45 mm, and sensation of well-being 46 mm. The median score for QoL was 47 and correlated well with the total ESAS score. Thirty-seven patients answered the open question "What in your current situation troubles you the most?". Seven patients answered "nothing", and 10 said "the present symptoms". Twenty patients had different concerns (existential, social, and psychological). The low number of hospitalised patients found reflects a well-functioning hospital-based home-care unit. Reduced appetite, sensation of well-being and activity were dominant, while pain and nausea were less intense. The simple QoL-VAS seemed to be comparable to ESAS, which is more useful for assessing each single symptom. The non-physical dimensions need more attention in the future in order to achieve totally satisfactory palliative care.


Energy and protein supplementation of ammoniated wheat straw diets for growing steers.
Eighty-eight yearling beef steers (308 +/- 1.4 kg) were used in two separate trials to determine the protein-sparing value of the N added to wheat straw during the ammoniation process and to determine the effects of supplementing ammoniated straw diets with energy and ruminal escape protein. In Exp. 1, steers were fed untreated straw (US) with either 0, 150, or 500 g of soybean meal (SBM) for 88 d. The addition of SBM to US diets increased (P less than .01) straw intake and average daily gains (ADG), indicating that N was limiting. When ammoniated straw (AS) was substituted for US, the N in the AS was used as efficiently as 500 g of SBM for growth. In Exp. 2, steers had ad libitum access to AS with three levels of supplemental corn (0, 1.23, or 2.45 kg DM.animal-1.d-1) either with or without .41 kg DM of corn gluten meal (CGM) added. Straw intake decreased (P less than .01) as the amount of corn in the diet was increased, but ADG increased (P less than .01) with the addition of corn. Straw consumption was not altered by the addition of CGM, but ADG was increased (P less than .01) by an average .35 kg by CGM. Rumen and blood N components indicated that the N from AS was contributing to the ruminal N pool and that CGM was compensating for microbial protein deficiencies postruminally.


RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway.
The Rothmund-Thomson syndrome (growth retardation, skin and bone defects, predisposition to cancer) and the RAPADILINO syndrome are caused by mutations in the RECQL4 gene. The 133 kDa RECQL4 is a putative DNA helicase, a member of the family that includes the BLM and WRN helicases. The latter are mutated, respectively, in the Bloom and Werner syndromes, whose manifestations include predisposition to cancer. Using antibodies to human RECQL4, we found that the bulk of RECQL4 was present in a cytoplasmic extract of HeLa cells, in contrast to the largely nuclear BLM and WRN helicases. However, in untransformed WI-38 fibroblasts, RECQL4 was found to be largely nuclear, and was present at significantly lower total levels than in transformed HeLa cells. RECQL4 from HeLa cells was isolated as a stable complex with UBR1 and UBR2. These 200 kDa proteins are ubiquitin ligases of the N-end rule pathway, whose substrates include proteins with destabilizing N-terminal residues. The functions of this proteolytic pathway include the regulation of peptide import, chromosome stability, meiosis, apoptosis and cardiovascular development. Although the known role of UBR1 and UBR2 is to mediate polyubiquitylation (and subsequent degradation) of their substrates, the UBR1/2-bound RECQL4 was not ubiquitylated in vivo, and was a long-lived protein in HeLa cells. The isolated RECQL4-UBR1/2 complex had a DNA-stimulated ATPase activity, but was inactive in DNA-based assays for helicases and translocases, the assays in which the BLM helicase was active. We discuss ramifications of these results, possible functions of RECQL4, and the involvement of the N-end rule pathway.


Efficacy and safety of corticosteroid therapy in patients with cardiac arrest: A meta-analysis of randomized controlled trials.
The clinical benefits of steroid therapy during cardiac arrest (CA) are unclear. Several recent clinical trials have shown that administering corticosteroid therapy during CA may improve patient outcomes. The purpose of the present study was to determine whether providing corticosteroids improves outcomes for patients following CA. We searched the PubMed, Embase, Cochrane Library, Web of Science and CNKI databases for randomized controlled trials comparing corticosteroid therapy to placebo during CA. Eleven relevant studies involving a total of 2273 patients were included in the meta-analysis. The statistical analysis showed that corticosteroid treatment during CA was significantly associated with an increased rate of sustained return of spontaneous circulation (ROSC) (OR: 2.05, 95% CI: 1.24 to 3.37, P < 0.01). Corticosteroid treatment during CA did not show a significant benefit in favorable neurological outcomes (OR: 1.13, 95% CI: 0.81 to 1.58, P = 0.49) or overall survival rate at hospital discharge (OR: 1.29, 95% CI: 0.74 to 2.26, P = 0.38). However, in the subgroup analysis, we found that patients had a significantly increased survival rate and ROSC if the dose of corticosteroid therapy above 100 mg methylprednisolone. The statistical analysis revealed no significant differences in adverse events. High-dose corticosteroid treatment (above 100 mg methylprednisolone) is associated with better overall survival rate at hospital discharge and ROSC outcomes. However, there is uncertainty regarding whether this treatment results in a benefit or harm to the favorable neurological outcomes at hospital discharge.


Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility.
To investigate the relation between reproductive age and ultrasound (US)-based follicle counts and the reproducibility of follicle counts in regularly cycling women with proven fertility. Prospective observational study. Tertiary fertility center. Healthy female volunteers with proven fertility, recruited by advertisement in local newspapers. The number of antral follicles sized 2-10 mm and ovarian volume were estimated by transvaginal US in the early follicular phase of the menstrual cycle in 162 women. A subgroup of 81 women underwent transvaginal US at several times in three subsequent cycles. Antral follicle count and total ovarian volume. Women aged 25-46 years (n = 162) were studied. The relation of age with the US indices was computed after natural log transformation. Antral follicle count showed the clearest correlation with age (R = -0.67). A biphasic linear model gave the best fit to the data. Before the age of 37 years, the antral follicle count showed a mean yearly decline of 4.8%, compared with 11.7% thereafter. The reproducibility of the antral follicle count in two subsequent cycles was moderate. The number of small antral follicles in both ovaries as measured by US is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool.


Effect of cleaning procedure and hygienic condition of milking equipment on bacterial count of bulk tank milk.
The aim of the study was to describe the characteristics of cleaning procedures for milking equipment applied in intensive dairy farms in Lombardy (Italy) and to study their relationships with bacterial count of bulk milk and hygienic condition of milking machine components. A group of 22 dairy farms was visited twice (winter and summer) in order to collect bulk tank milk and post-rinse water samples and swabs from liners and milk receiver. Samples were analysed to determine: standard plate count (SPC), laboratory pasteurization count (LPC), psychrotrophic bacteria count (PBC), coliform count (CC) and Escherichia coli. Cleaning procedures were monitored using electronic milk flow meters with specific software for the measurement of the duration of each cleaning phase, circulating solution temperature and electrical conductivity, turbulence and water filling percentage of pipelines. The results showed that farms classified as high and low milk total bacteria count significantly differed both in terms of liners and receiver bacterial contamination and in terms of water temperature reached during the detergent phase of cleaning milking equipment. Significant positive correlations were found among total bacteria count in milk and bacterial contamination of the liners. Maximum water temperature reached during the cleaning cycle of milking equipment was very low (34.4±8.9°C on average); most of the observations (88.6%) corresponded to water temperatures <45°C. Cleaning temperature was related to psychrotrophic bacteria count of milk and post-rinse water and coliform count in liners. Routine check and regulation of water temperature during the washing phase of the milking machine can be a simple and effective way to control one of the main risk factors for bacteriological quality of bulk tank milk.


Effects of emulsified isoflurane on haemodynamics and cardiomyocyte apoptosis in rats with myocardial ischaemia.
1. It has been shown that inhaled isoflurane limits the size of myocardial infarcts. The aim of the present study was to examine the effects of emulsified isoflurane on cardiac function and myocardial apoptosis in an ischaemia model of myocardial injury. 2. In the first study, 48 rats were randomly allocated to six groups (n = 8 in each): control (saline); emulsified isoflurane (EIso) at 1, 2 or 4 mL/kg; 30% intralipid (vehicle for EIso); and sham operated. Rats received isovolumetric intravenous infusions for 30 min and then, 30 min after cessation of the infusion, 90 min coronary occlusion. Haemodynamics and myocardial infarct size were measured. In the second study, another 48 rats were randomized into six groups (n = 8 in each). After 90 min ischaemia, rats were killed for histopathological study, immunohistochemical evaluation and apoptosis measurement. 3. Pretreatment with 2 and 4 mL/kg EIso significantly attenuated decreases in left ventricular systolic pressure and dP/dt(max), and increases in left ventricular end-diastolic pressure and -dP/dp(max), and alleviated myocardial injury compared with the control, intralipid and 1 mL/kg EIso groups (P < 0.05). Infusion of 1 mL/kg EIso and intralipid had no effect on haemodynamics, infarct size or histological variables. 4. Expression of Bcl-2 was increased, whereas expression of Bax and caspase 3 was decreased, after preconditioning with 2 and 4 mL/kg EIso (P < 0.05). The apoptotic index in the 2 and 4 mL/kg Eiso-treated groups was reduced compared with that in the control and intralipid groups (P < 0.01). 5. In conclusion, EIso ameliorates cardiac dysfunction, attenuates myocardial damage and inhibits apoptosis after ischaemia, which may be attributed, in part, to diminished expression of apoptosis-related protein.


Patients' Adherence to Recommended Follow-up Eye Care After Diabetic Retinopathy Screening in a Publicly Funded County Clinic and Factors Associated With Follow-up Eye Care Use.
The public health success of diabetic retinopathy (DR) screening programs depends on patients' adherence to the timetable of follow-up eye care recommended by the screening program. African Americans are among those at highest risk for DR and have one of the lowest rates of eye care use. To assess the rate of adhering to recommended follow-up eye care in a DR screening program administered in a safety-net health care facility and to examine factors associated with follow-up eye care use. Prospective follow-up study of persons with type 1 or type 2 diabetes. The setting was an internal medicine clinic of a publicly funded health system in Alabama, serving a population largely uninsured and African American, that had implemented a DR screening program using a nonmydriatic camera for ocular imaging and remote reading centers for evaluation of images. Patients with physician appointments between January 26 and July 24, 2012, were eligible for screening if they had a diagnosis of type 1 or type 2 diabetes and were 19 years or older. Data from the county health system's administrative database were obtained from January 26, 2012 (date of first enrollee), through May 1, 2015, to establish participants' eye care use in the ophthalmology clinic after screening. Adherence to the recommended interval of follow-up eye appointments in the facility's ophthalmology service as determined by administrative records, as well as factors associated with adherence. Diabetic retinopathy screening was completed in 949 adults with diabetes, of whom 84.5% (802 of 949) were African American, 64.5% (612 of 949) were women, and 71.7% (680 of 949) lacked health insurance. Participants ranged in age from 21 to 95 years, and their mean (SD) age was 53.9 (10.4) years. The mean (SD) age at diabetes diagnosis was 44.3 (12.5) years, and the mean (SD) duration of diabetes was 9.6 (9.4) years. Across interval recommendation types, 29.9% (284 of 949) adhered to obtaining comprehensive follow-up eye care within the recommended time frame. Two years after a participant's screening date, 50.9% (483 of 949) had no record of having received eye care. Factors associated with adhering to interval appointments were having an advanced age (odds ratio, 1.02; 95% CI, 1.01-1.04) and knowing one's glycated hemoglobin level (odds ratio, 2.00; 95% CI, 1.34-2.97). Agreeing to assistance in making a follow-up eye care appointment was associated with nonadherence (odds ratio, 0.67; 95% CI, 0.45-0.99). After a DR screening program in a public clinic largely serving an African American population, only one-third of participants adhered to interval recommendations for follow-up eye appointments, even though cost and accessibility were minimized as barriers to care. Our findings suggest that DR screening programs are not likely to meet their public health goals without incorporation of eye health education initiatives successfully promoting adherence to recommended comprehensive eye care for preventing vision loss.


General practitioner and mental healthcare use in a community sample of people with diagnostic threshold symptoms of bulimia nervosa, binge-eating disorder, and other eating disorders.
Lengthy delays in receiving treatment have been reported for people with bulimia nervosa (BN) and binge-eating disorder (BED). This study aimed to investigate healthcare use and predictors of mental health specialist healthcare use in a community sample of individuals with diagnostic threshold symptoms of BN, BED-Broad, or another eating disorder (Other ED). In 2017, 2,977 individuals aged ≥15 years were interviewed in a general population survey. Participants were asked questions relating to sociodemographic, ED symptoms, other clinical features, and healthcare use data. Assessment of ED symptoms was based on diagnostic questions derived from the eating disorder examination. Thirty-six participants with symptoms of BN, 33 participants with BED-Broad, and 369 with an Other ED were identified. Fewer people with symptoms of BN/BED-Broad (23%) or an Other ED (6%) had treatment from a mental health specialist than from a general practitioner (GP; 80%, 71.6%). Healthcare use differed significantly across type of ED only for treatment from a mental health specialist. In multivariate analyses, being asked about a person's mental health by a GP was the best explanatory variable for receiving treatment from a mental health specialist. A large treatment gap exists in healthcare for people with EDs. Inquiry about an individual's mental health by a GP was associated with higher rates of treatment from mental health specialists. However, a similar diet/eating inquiry did not have this association. Future research should consider the use of this patient and practitioner consultation in targeting improved detection of EDs.


Is there a superior occipitofrontal fasciculus? A microsurgical anatomic study.
Using a fiber-dissection technique, our aim was to expose and study the myelinated fiber bundles of the brain to achieve a clearer conception of their configurations and locations. During the course of our study, the superior occipitofrontal fasciculus became the focus of our interest. Many publications have defined this as a bundle of association fibers, located between the corpus callosum and the caudate nucleus, that connects the frontal and occipital lobes. By examining this area using fiber dissection, we realized that the descriptions of the anatomy are inadequate; thus, we focused on the elucidation of the anatomic structures of this region and, in particular, that known as the superior occipitofrontal fasciculus. Twenty previously frozen, formalin-fixed human brains were dissected under the operating microscope using the fiber-dissection technique. On coronal sections of the brain, a structure on the superolateral aspect of the caudate nucleus usually has been identified as the superior occipitofrontal fasciculus. However, our fiber dissections revealed that this structure is the superior thalamic peduncle, that it is composed of projection fibers rather than association fibers, and that it does not interconnect the occipital and frontal lobes. The structures of the brain are better understood when the fiber-dissection technique is used to explore their configurations and locations. The resulting information is especially beneficial for planning strategies and tactics of neurosurgical procedures.


Evaluating noninvasive genetic sampling techniques to estimate large carnivore abundance.
Monitoring large carnivores is difficult because of intrinsically low densities and can be dangerous if physical capture is required. Noninvasive genetic sampling (NGS) is a safe and cost-effective alternative to physical capture. We evaluated the utility of two NGS methods (scat detection dogs and hair sampling) to obtain genetic samples for abundance estimation of coyotes, black bears and Canada lynx in three areas of Newfoundland, Canada. We calculated abundance estimates using program capwire, compared sampling costs, and the cost/sample for each method relative to species and study site, and performed simulations to determine the sampling intensity necessary to achieve abundance estimates with coefficients of variation (CV) of <10%. Scat sampling was effective for both coyotes and bears and hair snags effectively sampled bears in two of three study sites. Rub pads were ineffective in sampling coyotes and lynx. The precision of abundance estimates was dependent upon the number of captures/individual. Our simulations suggested that ~3.4 captures/individual will result in a < 10% CV for abundance estimates when populations are small (23-39), but fewer captures/individual may be sufficient for larger populations. We found scat sampling was more cost-effective for sampling multiple species, but suggest that hair sampling may be less expensive at study sites with limited road access for bears. Given the dependence of sampling scheme on species and study site, the optimal sampling scheme is likely to be study-specific warranting pilot studies in most circumstances.


Methylation Profiling Identifies Epigenetic Markers for High-grade Gliomas.
Hypermethylation of CpG island is an epigenetic event prevalent in human gliomas. Here we employed a high-throughput microarray approach for a global search of DNA methylation to identify novel epigenetic loci in specific glioma subtypes. Hierarchical clustering analysis separated 20 glioma samples according to their WHO histopathological subtypes - pilocytic astrocytomas (PAs, grade I), oligoastrocytomas (OAs, grade II) and glioblastomas (GBMs, grade IV), based on their unique methylation patterns. The overall methylation frequency of the low-grade PAs was significantly less than that of the more aggressive OAs and GBMs (0.45% versus 2.0% and 1.4%; PAs versus OAs, p<0.01; PAs versus GBMs, p<0.01). The lower level of DNA methylation observed in PAs may be in part due to the increased methylation of multiple CpG islands which occur in more advanced tumors. However, the young age of onset of PAs may also contribute to this observed difference. Although there were many hypermethylated loci exclusive to the OA and GBM subtypes, the methylation frequencies between these groups were not significantly different. Analysis by methylation-specific PCR on an expanded set of samples and on more glioma subtypes further confirmed an epigenetic marker, SMARCA5, the hypermethylation of which was preferentially observed in grade IV, but not in grades I or II gliomas (p<0.0001). The intermediate grade III gliomas showed low levels of SMARCA5 hypermethylation. Epigenetic loci uncovered in the present study recapitulate the histopathological differences of these gliomas, indicating that these molecular changes may be responsible for the development of the different glioma subtypes. On-going work in our laboratory has shown that some of these loci are indeed hypermethylated in the early stages of astrocytic tumors.


Pneumocystis carinii induces ICAM-1 expression in lung epithelial cells through a TNF-alpha-mediated mechanism.
Inflammatory cell recruitment contributes to respiratory impairment during Pneumocystis carinii pneumonia. We evaluated expression of intercellular adhesion molecule-1 (ICAM-1), a key participant in leukocyte accumulation, in rats with P. carinii pneumonia. Immunostaining for ICAM-1 was most marked on bronchiolar epithelium but was also evident on type II pneumocytes, endothelium, and macrophages. Lung from normal and dexamethasone-treated uninfected animals exhibited markedly less ICAM-1. We hypothesized that P. carinii promoted ICAM-1 expression in epithelium through tumor necrosis factor-alpha (TNF-alpha) release from macrophages or that P. carinii directly stimulated ICAM-1 expression. Alveolar macrophages were incubated with P. carinii, and the medium was added to A549 epithelial cells. Treatment of macrophages with P. carinii enhanced A549 ICAM-1, which was inhibited with antibody to TNF-alpha. To determine whether P. carinii alone also stimulated ICAM-1, A549 cells were cultured with P. carinii, also augmenting ICAM-1. Of note, A549 ICAM-1 expression from P. carinii alone was less than with P. carinii-exposed macrophages. Thus ICAM-1 is enhanced in lung epithelium during P. carinii infection, in part, through TNF-alpha-mediated mechanisms.


Multiple system atrophy: a sporadic synucleinopathy.
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized clinically by varying degrees of Parkinsonism, cerebellar ataxia and autonomic dysfunction and pathologically by degeneration in the substantia nigra, putamen, olivary nucleus, pontine nuclei and cerebellum. In addition to selective neuronal loss, iron pigment accumulation and gliosis, myelin pathology is increasingly recognized. In affected white matter, myelin displays signs of degeneration and oligodendroglia contain argyrophilic inclusion bodies, so-called glial cytoplasmic inclusions (GCI). GCI are composed of 10-15-nm diameter coated filaments that are immunoreactive for ubiquitin and alpha-synuclein. Similar inclusions are occasionally found in neuronal cell bodies and cell processes in MSA. Given the presence of inclusion bodies composed of synuclein, it is reasonable to assume that biochemical alterations would be detected in synuclein in MSA and indeed this is the case. In MSA synuclein has biophysical properties that suggest increasing insolubility such as sedimentation in dense fractions in sucrose gradients and ready extraction into detergents and formic acid. Surprisingly, these biochemical modifications in synuclein are more widespread in the brain that the obvious pathology and suggest a fundamental molecular characteristic of the disorder. Similar neuronal, and less frequently glial, inclusions are detected in Lewy body disease, where there is also evidence for biophysical alterations in synuclein. Thus, MSA and LBD are both synucleinopathies, and they may comprise different poles of a disease spectrum that includes sporadic disorders as well as genetically determined disorders such as familial Lewy body Parkinsonism.


Immune response in overnutrition.
Nutritional modulation of the immune response can be demonstrated both in nutritional deficiency and in obesity. A proportion of obese adolescents and adults showed a variable impairment of cell-mediated immune responses in vivo and in vitro and reduction of intracellular bacterial killing by polymorphonuclear leukocytes. Immunological changes correlated with subclinical deficiencies of iron and zinc, and therapy with these micronutrients for 4 weeks resulted in improvement in immunological responses. In genetically obese mice, the number of mononuclear cells and Thy 1.2-positive lymphocytes in the thymus and the spleen is less compared with that in lean controls. The plaque-forming antibody response is reduced. Natural killer cell activity is increased. Cytotoxic response of spleen cells of obese animals immunized in vivo was markedly lower than that of lean controls, whereas the same response after in vitro sensitization was normal. These data point to the importance of metabolic and nutritional factors in the pathogenesis of altered immunocompetence.


Effects of intranasal oxytocin on distraction as emotion regulation strategy in patients with post-traumatic stress disorder.
Post-traumatic stress disorder (PTSD) is characterized by difficulty down-regulating emotional responses towards trauma-reminders. The neuropeptide oxytocin may enhance treatment response in PTSD, by dampening excessive fear and improving fear regulation. However, oxytocin effects on (neural correlates of) cognitive emotion regulation abilities have never been investigated in PTSD patients. Therefore, we investigated behavioral and neural effects of intranasal oxytocin administration (40IU) on distraction as emotion regulation strategy in male and female police officers with and without PTSD (n = 76), using a randomized placebo-controlled cross-over fMRI study. The distraction condition consisted of a working memory task while negative affective pictures were presented. Under placebo, male PTSD patients showed decreased right striatal activity during distraction compared to male trauma-exposed controls, which was unaffected by oxytocin. After oxytocin administration, left thalamus activity during distraction was enhanced in all participants, independent of PTSD status or sex. Although left thalamus activity during distraction did not differ between PTSD patients and controls under placebo, it was negatively correlated with error rates within PTSD patients. Furthermore, oxytocin administration increased functional connectivity between the left thalamus and amygdala in PTSD patients and male trauma-exposed controls. Upregulation of thalamus activity during distraction by oxytocin may enhance cognitive emotion regulation abilities during psychotherapy in PTSD, although this should still be investigated in a clinical setting. Our findings open an important research avenue into oxytocin effects on cognitive emotion regulation in PTSD and other psychiatric disorders characterized by deficient emotion regulation abilities. Registered in the Netherlands Trial Registry, registration number: NTR3516.


Combustion metamorphism in southern california.
In several places in Southern California bituminous sediments of the Monterey Formation-siliceous shales, phosphatic rocks, dolomites, and arkoses-were affected during the Pleistocene and as late as the l9th century by spontaneous subsurface combustion of organic matter, during which temperatures up to 1600 degrees C were reached. This oxidative heating (combustion metamorphism) affected rock complexes over areas of tens of square kilometers that tend to occur in clusters. As a result of these processes, the rocks recrystallized and partially melted to form pseudomagmas which intruded the country rocks. The chemical compositions of these melts differ from those of igneous magmas. Acid and intermediate siliceous melts as well as phosphatic melts have formed. These two types are generally immiscible. The following high-temperature minerals were determined: alpha- and beta-cristobalite, quartz, calcic plagioclase, diopsidic pyroxene, wollastonite, cordierite, graphite, fluorapatite, and fluorite; at lower temperature pyrite, gypsum, aragonite, calcite, jarosite, and hexahydrite crystallized.


Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways.
Survival signaling by the erythropoietin (Epo) receptor (EpoR) is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo. Here we used mouse models of acute and chronic stress, including a hypoxic environment and β-thalassemia, to identify two markedly different response dynamics for two erythroblast survival pathways in vivo. Induction of the antiapoptotic protein Bcl-x(L) is rapid but transient, while suppression of the proapoptotic protein Bim is slower but persistent. Similar to sensory adaptation, however, the Bcl-x(L) pathway "resets," allowing it to respond afresh to acute stress superimposed on a chronic stress stimulus. Using "knock-in" mouse models expressing mutant EpoRs, we found that adaptation in the Bcl-x(L) response occurs because of adaptation of its upstream regulator Stat5, both requiring the EpoR distal cytoplasmic domain. We conclude that survival pathways show previously unsuspected functional specialization for the acute and chronic phases of the stress response. Bcl-x(L) induction provides a "stop-gap" in acute stress, until slower but permanent pathways are activated. Furthermore, pathologic elevation of Bcl-x(L) may be the result of impaired adaptation, with implications for myeloproliferative disease mechanisms.


The fate of 8-methoxypsoralen photoinduced crosslinks in nuclear and mitochondrial yeast DNA: comparison of wild-type and repair-deficient strains.
In Saccharomyces cerevisiae, after 8-methoxypsoralen [8-(OMe)Ps] photoaddition, more crosslinks are induced per unit dose in mitochondrial DNA than in nuclear DNA. In wild-type cells treated in the exponential phase of growth, single- and double-strand breaks are produced during crosslink removal and then are rejoined upon postexposure incubation. The incision step is almost blocked in the rad 3-2 mutant, which is also defective in excision-repair of UV-induced (254 nm) pyrimidine dimers. The cutting of crosslinks from nuclear DNA is depressed in wild-type stationary-phase cells. This is correlated with a higher sensitivity of such cells to 8-(OMe)Ps photoinduced cell killing. The incision of crosslinks is dramatically reduced in mitochondrial DNA. The rejoining of single- and double-strand breaks is not only dependent on the product of the RAD51 gene (as shown by others) but also of the PSO2 gene. A correlation was found between the ability to recombine and strand rejoining. Therefore, as in bacteria, both the excision and the recombinational repair systems are involved in crosslink repair in yeast. However, double-strand breaks in yeast constitute repair intermediates which are not detected in Escherichia coli. The LD37 (dose necessary to induce a mean of one lethal hit per cell) corresponds to about 120 crosslinks per genome in exponential-phase cells of the wild type and to 1-2 crosslinks in the pso2-1 mutant.


Discrete Libraries of Amphiphilic Poly(ethylene glycol) Graft Copolymers: Synthesis, Assembly, and Bioactivity.
Poly(ethylene glycol) (PEG) is an important and widely used polymer in biological and pharmaceutical applications for minimizing nonspecific binding while improving blood circulation for therapeutic/imaging agents. However, commercial PEG samples are polydisperse, which hampers detailed studies on chain length-dependent properties and potentially increases antibody responses in pharmaceutical applications. Here, we report a practical and scalable method to prepare libraries of discrete PEG analogues with a branched, nonlinear structure. These lipid-PEG derivatives have a monodisperse backbone with side chains containing a discrete number of ethylene glycol units (3 or 4) and unique functionalizable chain ends. Significantly, the branched, nonlinear structure is shown to allow for efficient nanoparticle assembly while reducing anti-PEG antibody recognition when compared to commercial polydisperse linear systems, such as DMG-PEG2000. By enabling the scalable synthesis of a broad library of graft copolymers, fundamental self-assembly properties can be understood and shown to directly correlate with the total number of PEG units, nature of the chain ends, and overall backbone length. These results illustrate the advantages of discrete macromolecules when compared to traditional disperse materials.


[Planned dialysis and regular use of primary care by diabetic patients in the city of Belo Horizonte, Minas Gerais State, Brazil].
The objective was to analyze factors associated with planned initiation of dialysis in diabetic patients in the city of Belo Horizonte, Minas Gerais State, Brazil. This was a cross-sectional study of 250 diabetic patients who began dialysis between January 2006 and December 2007. Initiating dialysis with an arteriovenous fistula or in peritoneal dialysis was classified as planned initiation. The study targeted socio-demographic, clinical, and health services use variables using a semi-structured interview. Multivariate analysis used Poisson regression. Seventy per cent of the patients began dialysis on an unplanned basis, and 67% of those consulted had been referred to a nephrologist more than four months previously. Attending a health center, not having the first nephrology appointment paid for by the Brazilian Unified National Health System, and having a choice of treatment for the kidney disease were associated with planned initiation of dialysis. Unplanned initiation of dialysis is common in the city of Belo Horizonte and occurs regardless of the time since referral to the nephrologist.


The pathogenesis of type II diabetes mellitus. A polygenic disease.
Diabetes mellitus is the most common endocrine disease, consuming almost 15% of annual health care expenditures in the United States. The focus of this review is on type II (non-insulin-dependent) diabetes mellitus, which accounts for approximately 90% of diabetic patients. The current understanding of the pathogenesis of type II diabetes is multifaceted. Complex defects in both insulin action and insulin secretion produce the metabolic derangements responsible for the disease. The pathophysiology is the result of a combination of polygene defects and environmental factors. The search for the responsible gene or genes is described and several candidate genes are discussed. Diabetogenes are addressed in the context of type II diabetes representing a prototype for the identification of the genetic basis of common diseases.


Recruitment of older participants in frailty/injury prevention studies.
Despite the lifelong health benefits of physical activity, frailer older adults have typically been excluded from studies promoting more active lifestyles. This study documents the recruitment process and costs from a multisite study to identify effective strategies for recruiting older adults in frailty/injury prevention research. Randomized controlled clinical trials were conducted at 7 sites; an 8th site was a compliance study. Interventions reflected center- and home-based health promotion programs. Site objectives, eligibility criteria, and contact and screening methods were obtained from manuals of operation. Recruitment results (number screened, eligibility rates, randomized to screened ratios) were ascertained from recruitment data. Sites furnished estimated recruitment costs (nonlabor expenses, investigator and staff time, fringe benefits) up to signing the consent form. The sites targeted diverse populations and sample sizes. The majority revised recruitment methods to meet their recruitment goals. Most sites estimated costs of recruitment at over $300 per participant randomized. Recruitment costs were affected by staff time spent alleviating concerns about participants' health, essential interactions with family members, and arranging for transportation. Neither frailty nor intervention intensity was found to be a major predictor of recruitment outcomes. Recruitment expense was associated with selection criteria and frailty status of the target population. Older people can be successfully recruited into beneficial health promotion programs, but it is often challenging. In planning health promotion studies, investigators need to be aware of the numbers of older people they may need to screen and different strategies for increasing recruitment success.


Access to Federally Qualified Health Centers and Emergency Department Use Among Uninsured and Medicaid-insured Adults: California, 2005 to 2013.
While improved access to safety net primary care providers, like federally qualified health centers (FQHCs), is often cited as a route to alleviate potentially preventable emergency department (ED) visits, no studies have longitudinally established the impact of improving access to FQHCs on ED use among Medicaid-insured and uninsured adults. We aimed to determine whether improved access to FQHCs was associated with lower ED use by uninsured and Medicaid-insured adults. Using data from the Uniform Data System, U.S. Census Bureau, and California Office of Statewide Health Planning & Development, we conducted a longitudinal analysis of 58 California counties from 2005 to 2013. For each county-year observation, we employed three measures of FQHC access: geographic density of FQHCs (delivery sites per 100 square miles), FQHCs per county resident (delivery sites per 100,000 county residents), and the proportion of Medicaid-insured or uninsured residents ages 19 to 64 years that utilized FQHCs. We then used a fixed-effects model to examine the impact of changes in the measures of FQHC access on ED visit rates by Medicaid-insured or uninsured adults in each county. Increasing geographic density of FQHCs was associated with a 26% to 35% decrease in ED use by uninsured but not Medicaid-insured patients. Increasing numbers of clinics per county resident and higher percentages of Medicaid-insured and uninsured adults seen at FQHCs were not associated with reduced rates of ED use among either uninsured or Medicaid-insured adults. We were unable to detect a consistent association between our measures of FQHC access and ED use by Medicaid-insured and uninsured nonelderly California adults, underscoring the importance of investigating additional drivers to reduce ED use among these vulnerable patient populations.


Hyperoxia affects the regional pulmonary ventilation/perfusion ratio: an electrical impedance tomography study.
The way in which hyperoxia affects pulmonary ventilation and perfusion is not fully understood. We investigated how an increase in oxygen partial pressure in healthy young volunteers affects pulmonary ventilation and perfusion measured by thoracic electrical impedance tomography (EIT). Twelve semi-supine healthy male volunteers aged 21-36 years were studied while breathing room air and air-oxygen mixtures (FiO2) that resulted in predetermined transcutaneous oxygen partial pressures (tcPO2) of 20, 40 and 60 kPa. The magnitude of ventilation (ΔZv) and perfusion (ΔZQ)-related changes in cyclic impedance variations, were determined using an EIT prototype equipped with 32 electrodes around the thorax. Regional changes in ventral and dorsal right lung ventilation (V) and perfusion (Q) were estimated, and V/Q ratios calculated. There were no significant changes in ΔZv with increasing tcPO2 levels. ΔZQ in the dorsal lung increased with increasing tcPO2 (P = 0.01), whereas no such change was seen in the ventral lung. There was a simultaneous decrease in V/Q ratio in the dorsal region during hyperoxia (P = 0.04). Two subjects did not reach a tcPO2 of 60 kPa despite breathing 100% oxygen. These results indicate that breathing increased concentrations of oxygen induces pulmonary vasodilatation in the dorsal lung even at small increases in FiO2. Ventilation remains unchanged. Local mismatch of ventilation and perfusion occurs in young healthy men, and the change in ventilation/perfusion ratio can be determined non-invasively by EIT.


A methodological approach for the biomechanical cause analysis of golf-related lumbar spine injuries.
A new methodological approach employing mechanical work (MW) determination and relative portion of its elemental analysis was applied to investigate the biomechanical causes of golf-related lumbar spine injuries. Kinematic and kinetic parameters at the lumbar and lower limb joints were measured during downswing in 18 golfers. The MW at the lumbar joint (LJ) was smaller than at the right hip but larger than the MWs at other joints. The contribution of joint angular velocity (JAV) to MW was much greater than that of net muscle moment (NMM) at the LJ, whereas the contribution of NMM to MW was greater rather than or similar to that of JAV at other joints. Thus, the contribution of JAV to MW is likely more critical in terms of the probability of golf-related injury than that of NMM. The MW-based golf-related injury index (MWGII), proposed as the ratio of the contribution of JAV to MW to that of NMM, at the LJ (1.55) was significantly greater than those at other joints ( < 1.05). This generally corresponds to the most frequent occurrence of golf-related injuries around the lumbar spine. Therefore, both MW and MWGII should be considered when investigating the biomechanical causes of lumbar spine injuries.


Dopaminergic systems create reward seeking despite adverse consequences.
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.


Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer.
Since the 2015 WHO classification was introduced into clinical practice, immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small cell versus non-small cell carcinoma, patients' treatment of choice is directly linked to histologic subtypes of non-small cell carcinoma, which pertains to IHC results, particularly for poorly differentiated tumors. The use of IHC has improved diagnostic accuracy in the classification of lung carcinoma, but the interpretation of IHC results remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The International Association for the Study of Lung Cancer Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several International Association for the Study of Lung Cancer Pathology Committee meetings, the issues and caveats were summarized in terms of 11 key questions covering common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions cover topics such as the best IHC markers for distinguishing NSCLC subtypes, differences in thyroid transcription factor 1 clones, and the utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors. This article provides answers and explanations for the key questions about the use of IHC in diagnosis of lung carcinoma, representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.


A Tablet-Based Retinal Function Test in Neovascular Age-Related Macular Degeneration Eyes and At-Risk Fellow Eye.
To determine the feasibility of a tablet-based application to detect changes in retinal sensitivity and correlations with underlying pathology in neovascular age-related macular degeneration (nAMD) eyes undergoing treatment and in at-risk fellow eyes. Participants with nAMD in at least one eye were recruited, examined, and imaged using spectral-domain optical coherence tomography (SD-OCT). Retinal sensitivity was measured within the central 5° at 12 locations using a customized test delivered on an iPad. Test points were superimposed on SD-OCT locations to investigate structure/function relationships. Included in the study were 53 nAMD eyes and 21 at-risk fellow eyes. In nAMD eyes, the mean retinal sensitivity was 24.1 ± 1.8 dB with reduced retinal sensitivity associated with the presence of atrophy (P < 0.01), retinal pigment epithelium (RPE) disruption (P < 0.01), and absent ellipsoid zone (EZ) (P < 0.01), but not with the presence of subretinal fluid (P = 0.94) nor intraretinal fluid (P = 0.52). In at-risk eyes, the average retinal sensitivity was 28.8 ± 0.6 dB, with reduced sensitivity significantly associated with the presence of drusen, atrophy, RPE disruption, and absent EZ (P < 0.01). The tablet-based test of retinal sensitivity was able to be performed by an elderly cohort with nAMD. The ability to correlate differences in sensitivity with pathology is encouraging when considering using the tablet devices as a home monitoring tool with remote surveillance. Dual pathology often present with retinal fluid confounded our ability to correlate fluid with sensitivity. These findings highlight the potential of tablet-based devices in performing visual function measures as a home monitoring tool with remote surveillance for the earlier detection of nAMD.


Characterization of a second bovine rotavirus serotype.
Bovine rotavirus (BRV) V 1005 was characterized by two-way cross-neutralization tests as a second serotype of BRV. Virions and inner shell particles of 65 nm and 55 nm diameter respectively, and empty capsids of 65 nm and 55 nm diameter were separated by density gradient centrifugation. Three polypeptides of molecular weight 60,000, 36,000 and 28,000 (minor protein) could be identified in the outer shell of virions and in the larger empty capsids. Inner shell particles contained three polypeptides of molecular weight 105,000, 83,000 and 43,000. Both sizes of empty capsids showed two polypeptides of molecular weight 75,000 and 55,000 not found in virions. Pulse-labelling of infected cells revealed eight major and three minor intracellular viral polypeptides. Viral polypeptides synthesis started at about 6 hours p.i. and correlated in time with double-stranded RNA synthesis. As soon as viral polypeptide synthesis was detectable, newly synthesized viral polypeptides were incorporated into intracellular viral particles. Radioactive viral polypeptides appeared without a longer lag period in extracellular viruses from 6 hours p.i. onwards.


Observations on sex ratio and behavior of males in Xyleborinus saxesenii Ratzeburg (Scolytinae, Coleoptera).
Strongly female-biased sex ratios are typical for the fungalfeeding haplodiploid Xyleborini (Scolytinae, Coleoptera), and are a result of inbreeding and local mate competition (LMC). These ambrosia beetles are hardly ever found outside of trees, and thus male frequency and behavior have not been addressed in any empirical studies to date. In fact, for most species the males remain undescribed. Data on sex ratios and male behavior could, however, provide important insights into the Xyleborini's mating system and the evolution of inbreeding and LMC in general.In this study, I used in vitro rearing methods to obtain the first observational data on sex ratio, male production, male and female dispersal, and mating behavior in a xyleborine ambrosia beetle. Females of Xyleborinus saxesenii Ratzeburg produced between 0 and 3 sons per brood, and the absence of males was relatively independent of the number of daughters to be fertilized and the maternal brood sex ratio. Both conformed to a strict LMC strategy with a relatively precise and constant number of males. If males were present they eclosed just before the first females dispersed, and stayed in the gallery until all female offspring had matured. They constantly wandered through the gallery system, presumably in search of unfertilized females, and attempted to mate with larvae, other males, and females of all ages. Copulations, however, only occurred with immature females. From galleries with males, nearly all females dispersed fertilized. Only a few left the natal gallery without being fertilized, and subsequently went on to produce large and solely male broods. If broods were male-less, dispersing females always failed to found new galleries.


Samarium(II)-mediated reactions of gamma,delta-unsaturated ketones. Cyclization and fragmentation processes.
[reaction: see text] On treatment with samarium(II) iodide, gamma,delta-unsaturated ketones undergo very different processes depending upon the nature of the reaction conditions. Employing samarium(II) iodide and MeOH, functionalized syn-cyclopentanol products are obtained stereoselectively. Mechanistic studies suggest that this cyclization occurs via a sequential reduction/intramolecular aldol reaction. With samarium(II) iodide and HMPA, products of a 4-exo-trig cyclization and of an interesting fragmentation reaction are observed.


Analysis of Somatostatin-Secreting Gastric Delta Cells according to Upper Abdominal Symptoms and Helicobacter pylori Infection in Children.
Gastric delta cells (D-cells), which are somatostatin-secreting cells, are the main paracrine inhibitor of acid secretion. The number of D-cells was studied in children presenting with upper gastrointestinal (UGI) disease. We retrospectively investigated the number of D-cells in the gastric body and antrum through immunofluorescence examinations according to symptoms, endoscopic findings, and Helicobacter pylori infection in 75 children who visited Hanyang University Hospital Pediatrics. The mean patient age was 12.2±3.3 years. The male-to-female ratio was 1:1.4. The mean D-cell number per high-power field in the antrum and body was 20.5 and 12 in children with substernal pain, 18.3 and 10.3 in vomiting, 22.3 and 6 in diarrhea, and 9.3 and 6 in abdominal pain, respectively (p>0.05). According to endoscopic findings, the mean D-cell number in the antrum and body was 14.3 and 6 with gastritis, 14 and 9.3 with reflux esophagitis, 16.7 and 8.7 with duodeno-gastric reflux, 19.3 and 12.7 with gastric ulcer, 16 and 13.7 with duodenitis, and 12.3 and 4 with duodenal ulcer, respectively (p>0.05). The D-cell number in the gastric body was 2.7 and 8.7 in children with current H. pylori infection and non-infected children, respectively (p=0.01), while those in the antrum were 15.5 and 14, respectively, with no statistical significance. The D-cell number was lower in the gastric body of children with current H. pylori infection. Further studies concerning peptide-secreting cells with a control group would provide information about the pathogenic pathways of UGI disorder.


Assays for determination of HIV resistance to antiviral drugs.
Resistance to antiretroviral drugs is one of the major pitfalls of combined treatment of HIV infection. Thus, timely identification of drug resistant HIV strains and precise evaluation of the level of resistance to the different antiretroviral drugs are crucial in the management of treated patients. Phenotypic determination of antiretroviral drug resistance evaluates the ability of an HIV strain to replicate in the presence of drug(s). Thus, this assay (either conventional or recombinant) provides a direct estimate of drug susceptibility. However, it is relatively difficult to perform and requires dedicated facilities. Thus, its use is still restricted. Genotypic determination of drug resistance is based upon detection of specific mutations in HIV genes encoding target enzymes or receptors. The assay provides an indirect evidence of drug susceptibility. However, it is easy to perform and does not require dedicated facilities. Thus, it is widely utilized in clinical practice. Its major limitation concerns the complexity of results interpretation which still awaits a general consensus.


Afterpulsing and its correction in fluorescence correlation spectroscopy experiments.
Afterpulsing arises from feedback in a photon detector. This means that each real signal pulse can be followed by an afterpulse at a later time. This effect is particularly troubling in photon correlation experiments. Few treatments of this effect have appeared in the literature, and few software programs to solve the problem have been written. We demonstrate the afterpulsing effect in fluorescence correlation spectroscopy by using different avalanche photodiodes. We prove theoretically that under simple and reasonable conditions afterpulsing in autocorrelation can be eliminated to the leading order; we have found it easy to program software for the correction. We compare our results with those from cross correlation. We also discuss some experimental parameters that may affect the afterpulsing.


The Relation Between Steroid Secretion Patterns and the Androgen Receptor Gene Polymorphism on Physical Health and Psychological Well-Being-Longitudinal Findings From the Men's Health 40+ Study.
Research is increasingly focusing on promoting healthy aging and the related extension of the health span by targeting crucial biological processes responsible for age-related conditions. While age-related gradual changes in steroid hormones such as testosterone, estradiol, or cortisol are well described in men, their interactions among each other or with genetic markers have not been sufficiently investigated with regard to physical health or psychological well-being. More specifically, the examination of age-related alterations in hormone interactions and the androgen receptor polymorphism, which modulates androgen action on target cells, in relation to physical health and psychological well-being represents a promising avenue for research on healthy aging in men. A total of 97 healthy aging men provided complete data on psychometric health measures as well as hormonal and genetic parameters at baseline and a 4-year follow-up assessment. Fasting saliva samples were taken at 8:00 am under standardized laboratory conditions, while the androgen receptor gene polymorphism was analyzed from dried blood spots. Longitudinal analyses revealed that psychological well-being and physical health remained stable over time. Analyses indicated that E2 moderated the course of psychological well-being, while the androgen receptor gene polymorphism moderated the course of physical health. Further, T was a strong predictor of physical health. These results suggest that the hypothalamic-pituitary-gonadal (HPG) axis might be important for the maintenance of psychological well-being in men, while physical health depends more on interindividual differences in the androgen receptor gene and T.


GABA(A) receptor subtype selective cognition enhancers.
Currently the treatment of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) is largely unrealised, with no preventive or curative therapies. The marketed acetylcholinesterase inhibitors (eg. donepezil, Aricept) are directed toward temporary symptomatic relief from impaired cognition, but have prominent adverse effects with minimal efficacy. In pursuit of novel cognition enhancers, the observation that classical benzodiazepines (BZ, eg. diazepam) are amnesic, coupled with the preservation of GABA(A) receptors in brain areas most affected by AD, highlighted the GABA(A) receptor as a potential therapeutic target. In contrast to the amnesic BZ agonists, the BZ inverse agonists (eg. DMCM) which attenuate GABA(A) receptor function, have been shown to improve performance in animal models of learning and memory. Unfortunately, such non-selective ligands also induce anxiety and convulsions. More recently, novel ligands have been developed (eg. 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one) that demonstrate binding selectivity and high inverse agonism for the alpha5 GABA(A) receptor subtype, which is preferentially located in the hippocampus, a region of the brain associated with learning and memory. Pre-clinical results are encouraging, since these alpha5 selective inverse agonists enhance memory in animal models, such as spatial learning in the Morris water-maze, but are devoid of the adverse effects associated with activity at other GABA(A) receptor subtypes in other brain regions. If the efficacy and safety profiles of alpha5 inverse agonists in humans prove to be similar to those seen in pre-clinical studies, these compounds would offer significant benefit to AD and MCI patients.