Relations between liver cadmium, cumulative exposure, and renal function in cadmium alloy workers.
Detailed biochemical investigations of renal function were made on 75 male workers exposed to cadmium and an equal number of referents matched for age, sex, and employment status. The exposed group consisted of current and retired workers who had been employed in the manufacture of copper-cadmium alloy at a single factory in the United Kingdom for periods of up to 39 years and for whom cumulative cadmium exposure indices could be calculated. In vivo measurements of liver and kidney cadmium burden were made on exposed and referent workers using a transportable neutron activation analysis facility. Significant increases in the urinary excretion of albumin, retinol binding protein, beta 2 microglobulin, N-acetylglucosaminidase (NAG), alkaline phosphatase, gamma-glutamyl transferase and significant decreases in the renal reabsorption of calcium, urate, and phosphate were found in the exposed group compared with the referent group. Measures of glomerular filtration rate (GFR) (creatinine clearance, serum creatinine, and beta 2 microglobulin) indicated a reduction in GFR in the exposed population. Many of these tubular and glomerular function indicators were significantly correlated with both cumulative exposure index and liver cadmium burden. Using cumulative exposure index and liver cadmium as estimates of dose, a two phase linear regression model was applied to identify an inflection point signifying a threshold level above which changes in renal function occur. Many biochemical variables fitted this model; urinary total protein, retinol binding protein, albumin, and beta 2 microglobulin gave similar inflection points at cumulative exposure levels of about 1100 y.micrograms/m3 whereas changes in the tubular reabsorption of urate and phosphate occurred at higher cumulative exposure indices. Measures of GFR, although fitting the threshold model did not give well defined inflection points. Fewer variables fitted the two phase model using liver cadmium; those that did gave threshold levels in the range 20.3-55.1 ppm. When cadmium workers with cumulative exposure indices of less than 1100 y.micrograms/m3 were compared with their respective referents only serum beta 2 microglobulin and urinary NAG were significantly increased in the exposed group and these differences were not related to the degree of cadmium exposure.(ABSTRACT TRUNCATED AT 400 WORDS)


Multi-stage inhibition in breast cancer metastasis by orally active triple conjugate, LHTD4 (low molecular weight heparin-taurocholate-tetrameric deoxycholate).
Targeting multiple stages in metastatic breast cancer is one of the effective ways to inhibit metastatic progression. To target human metastatic breast cancer as well as improving patient compliance, we developed an orally active low molecular weight heparin (LMWH)-taurocholate conjugated with tetrameric deoxycholic acid, namely LHTD4, which followed by physical complexation with a synthetic bile acid enhancer, DCK. In breast cancer, both transforming growth factor-β1 (TGF-β1) and CXCL12 exhibit enhanced metastatic activity during the initiation and progression stages of breast cancer, thus we direct the focus on investigating the antimetastatic effect of LHTD4/DCK complex by targeting TGF-β1 and CXCL12. Computer simulation study and SPR analysis were performed for the binding confirmation of LHTD4 with TGF-β1 and CXCL12. We carried out in vitro phosphorylation assays of the consecutive receptors of TGF-β1 and CXCL12 (TGF-β1R1 and CXCR4, respectively). Effects of LHTD4 on in vitro cell migration (induced by TGF-β1) and chemotaxis (mediated by CXCL12) were investigated. The in vivo anti-metastatic effect of LHTD4 was evaluated in an accelerated metastasis model and an orthotopic MDA-MB-231 breast cancer model. The obtained KD values of TGF-β1 and CXCL12 with LHTD4 were 0.85 and 0.019 μM respectively. The simulation study showed that binding affinities of LHTD4 fragment with either TGF-β1 or CXCL12 through additional electrostatic interaction was more stable than that of LMWH fragment. In vitro phosphorylation assays of TGF-β1R1 and CXCR4 showed that the effective inhibition of receptor phosphorylation was observed with the treatment of LHTD4. The expressions of epithelial to mesenchymal transition (EMT) marker proteins such as vimentin and Snail were prevented by LTHD4 treatment in in vitro studies with TGF-β1 treated MDA-MB-231 cells. Moreover, we observed that LHTD4 negatively regulated the functions of TGF-β1 and CXCL12 on migration and invasion of breast cancer cell. In several advanced orthotopic and experimental breast cancer metastasis murine models, the treatment with LHTD4 (5 mg/kg daily, p.o.) significantly inhibited metastasis compared to the control. Overall, LHTD4 exhibited anti-metastatic effects by inhibiting TGF-β1 and CXCL12, and the clinically relevant dose of orally active LHTD4 was found to be effective in preclinical studies without any apparent toxicity.


Comparison of pulmonary function and respiratory symptoms in water pipe and cigarette smokers.
A major type of smoking in Middle Eastern countries is water pipe (WP) smoking. In the present study, pulmonary function tests (PFT) and respiratory symptoms (RS) were compared in WP smokers and deep inspiration (S-DI) or normal inspiration (S-NI) cigarette smokers. Pulmonary function and RS were compared among WP smokers, deep or normal inspiration cigarette smokers, and non-smokers. All PFT values in WP smokers and S-DI, but only some values in S-NI, were lower than those of non-smokers (P < 0.05 to P < 0.001). In addition, all PFT values in WP smokers and S-DI were lower than the corresponding values in S-NI, except for forced expiratory volume in 1 s and maximal expiratory flow at 25% of forced vital capacity (P < 0.05 to P < 0.001). The prevalence of RS, except for sputum production, was greater in all three groups of smokers than in non-smokers (P < 0.05 to P < 0.001). However, the severity of most RS in WP smokers and S-DI, but only the severity of wheezing in S-NI, was greater than that in non-smokers (P < 0.05 to P < 0.01). There were inverse correlations for PFT values and positive correlations for RS, with duration and total amount of smoking (P < 0.05 to P < 0.001). The results from this study showed that there was a profound effect of WP smoking on PFT values and RS, which were similar to the effects of deep inspiration cigarette smoking.


Traumatic brain injury: oxidative stress and neuroprotection.
A vast amount of circumstantial evidence implicates high energy oxidants and oxidative stress as mediators of secondary damage associated with traumatic brain injury. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain. Different integrated responses exist in the brain to detect oxidative stress, which is controlled by several genes termed vitagens. Vitagens encode for cytoprotective heat shock proteins, and thioredoxin and sirtuins. This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma.


Histological inflammatory cell infiltration is associated with the number of lymph nodes retrieved in colorectal cancer.
Antitumor immune response is suggested to be a factor affecting the number of nodes retrieved after colorectal cancer surgery. The purpose of this study was to evaluate the correlation of antitumor immune response with the number of retrieved nodes. Patients with colorectal cancer (n=63, TNM stage II and III) were enrolled. Inflammatory cell infiltration (ICI) was assessed on hematoxylin and eosin staining and T-cell markers (CD3, CD8, CD45RO) were evaluated using immunohistochemical methods. On univariate analysis, high ICI, CD3 and CD8 expression were associated with a greater number of nodes being retrieved. On multivariate analysis, tumors of the right colon (p=0.01) and high ICI (p=0.04) were independent predictors of a greater retrieval of nodes. TNM stage III tumor with low ICI was associated with reduced cancer-specific survival (p=0.02). ICI influences the number of nodes retrieved and affects survival of patients with stage III disease. Antitumor immune response may be an underlying factor determining the number of nodes retrieved after surgery for colorectal cancer.


Informal carers--the role of general practitioners and district nurses.
Six million informal carers provide support for aged and disabled people in the United Kingdom. Government policies suggest that primary care teams are the main support for carers. This postal survey of 300 general practitioners (GPs) and 272 district nurses (DNs) aimed to determine current practice and views on their role in supporting informal carers. In practice, GPs and DNs lack time, resources, and training to provide support, and see themselves in a reactive role only.


Pain expectations in neuropathic pain: Is it best to be optimistic?
Pain expectancy may be an important variable that has been found to influence the effectiveness of treatments for pain. Much of the literature supports a self-fulfilment perspective where expectations for pain relief predict the actual pain experienced. However, in conditions such as neuropathic pain (NeP) where pain relief is difficult to attain, expectations for pain relief could be unrealistic. The objective of this study was to investigate the relationship between realistic/unrealistic expectations and 6-month, post-treatment outcomes. We performed a retrospective analysis of a large cohort of patients with NeP (n = 789) attending tertiary care centres to determine the association between unrealistic (both positive and negative) and realistic expectations with outcomes after multidisciplinary treatment. An expectation variable with three categories was calculated: realistic expectations were those whose expected reduction in pain was similar to the observed mean group reduction in pain, while optimistic and pessimistic expectations were those who over- or under-estimated the expected response to treatment, respectively. The association between baseline realistic/unrealistic expectations and 6-month pain-related disability, catastrophizing and psychological distress was assessed. Univariable analyses suggested that realistic expectations were associated with lower levels of disability, catastrophizing and psychological distress, compared to unrealistic expectations. However, after adjustment for baseline symptom severity, multivariable analysis revealed that patients with optimistic expectations had lower levels of disability, than those with realistic expectations. Those with pessimistic expectations had higher levels of catastrophizing and psychological distress at follow-up. These findings are largely congruent with the self-fulfilment perspective to expectations. This study defined realistic pain expectations with patient data. Examining the relationship between expectations between pain and disability in a large cohort of patients with neuropathic pain.


Domain-specific cognitive effects of white matter pathology in old age, mild cognitive impairment and Alzheimer's disease.
Concomitant white matter (WM) brain pathology is often present in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cognitive effects of WM pathology on cognition in normal and pathological aging have been studied, but very little is known about possible group-specific effects in old age, MCI and AD. The purpose of the current study was to examine the relationship between WM pathology and cognitive functioning in four cognitive domains in old age, MCI and AD. The study utilized multi-domain neuropsychological data and visually rated MRI imaging data from a sample of 56 healthy older adults, 40 patients with MCI and 52 patients with AD (n = 148). After controlling for age and education, main effects of frontal WM pathology (especially in the left hemisphere) were found for cognitive performances in two domains, whereas a main effect of parieto-occipital WM pathology was only found for processing speed. In addition, with regard to processing speed, an interaction between group and WM changes was found: Patients with AD that had moderate or severe left frontal WM pathology were considerably slower than patients with AD that had milder cerebrovascular pathology. Frontal WM pathology, especially in the left hemisphere, seems to affect cognitive functions in many domains in all three groups. The results of the study increase our knowledge of cognitive repercussions stemming from frontal and/or parieto-occipital WM pathology in AD. Clinicians should be aware that patients with AD with prominent frontal cerebrovascular pathology can have considerably slowed cognitive processing.


Antioxidants and Nanotechnology: Promises and Limits of Potentially Disruptive Approaches in the Treatment of Central Nervous System Diseases.
Many central nervous system (CNS) diseases are still incurable and only symptomatic treatments are available. Oxidative stress is suggested to be a common hallmark, being able to cause and exacerbate the neuronal cell dysfunctions at the basis of these pathologies, such as mitochondrial impairments, accumulation of misfolded proteins, cell membrane damages, and apoptosis induction. Several antioxidant compounds are tested as potential countermeasures for CNS disorders, but their efficacy is often hindered by the loss of antioxidant properties due to enzymatic degradation, low bioavailability, poor water solubility, and insufficient blood-brain barrier crossing efficiency. To overcome the limitations of antioxidant molecules, exploitation of nanostructures, either for their delivery or with inherent antioxidant properties, is proposed. In this review, after a brief discussion concerning the role of the blood-brain barrier in the CNS and the involvement of oxidative stress in some neurodegenerative diseases, the most interesting research concerning the use of nano-antioxidants is introduced and discussed, focusing on the synthesis procedures, functionalization strategies, in vitro and in vivo tests, and on recent clinical trials.


Influence of aflibercept on platelet activation profile.
Aflibercept appears to accumulate in systemic circulation following intravitreal injections in therapy of neovascular age-related macular degeneration. This gives raise to the question of whether aflibercept affects platelets and their function such as activation and aggregation, which are substantial in the pathogenesis of an arterial thromboembolic event (ATE). In order to determine the effect of aflibercept in platelet activation, platelets from healthy volunteers were treated with aflibercept and its solvents at equal concentrations (0.04 μg/mL - 4 μg/mL - 40 μg/mL - 400 μg/mL - 4 mg/mL) for 10 and 30 min before addition of agonists. IgG1 antibody was used as a control. The surface expression of GPIIb/IIIa, P-selectin, and platelet-bound stromal-cell-derived factor-1, which are potential blood biomarkers for ATEs, was determined on resting and activated platelets by the multispectral imaging flow cytometry, combining the features of flow cytometry with fluorescence microscopy. Platelet aggregation was assessed with light transmission aggregometry. To determine whether aflibercept directly interacts with platelets, aflibercept was labeled with the fluorescence FITC. Co-treatment of platelets with thrombin or PAR-4-AP and aflibercept resulted in increased activation of the fibrinogen receptor GPIIb/IIIa in comparison to controls (P < 0.05). Interestingly, the expression of platelet-derived P-selectin and SDF-1 was not affected by aflibercept, except thrombin-activated CD62P with 0.04 μg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.54, IC = 1.201-1.879 vs. MSI = 1.37, IC = 1.136-1.604 [P = 0.031]) and SDF-1 with 4 mg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.971, IC = 1.206-2.737 vs. MSI = 1.200, IC = 0.738-1.662 [P = 0.041]). Although the levels of platelet-bound aflibercept-FITC were significantly increased in all activated platelets, no effect was observed in platelet aggregation. Albeit no impact of aflibercept was found on platelet aggregation under the studied experimental conditions, the increased activation of the fibrinogen receptor GPIIb/IIIa and the presence of a direct interaction between aflibercept and platelets may partially explain the risk of ATE in patients under aflibercept treatment due to FcγRIIa mediated αIIbβ3 outside-in integrin signaling and transport of aflibercept into platelets. Therefore, the Fc domain seems to be involved in interactions between aflibercept and platelets. Further research is needed to explain the role of Fc containing aflibercept in the pathogenesis of drug-associated vascular events involving platelets, coagulation cascade, extracellular matrix proteins and other cells.


Design, Synthesis and Structure-Activity Relationships of (±)-Isochaihulactone Derivatives.
Z-K8 (2), the racemic form of isochaihulactone (1), previously showed significant antitumor effects in A549 and LNCaP tumor-bearing mice. In the present study, 17 derivatives of 2, were designed, synthesized and evaluated for anti-proliferative activity against four human tumor cell lines. All new derivatives exhibited high potency against A549 and P-glycoprotein (P-gp)-overexpressing KBvin. One of our new derivative exhibited greater activity against three tested tumor cells (A549, KB, and KB-VIN) than 2, and induced cell cycle arrest in the G2/M phase. Moreover, SAR conclusions were first established for this series of compounds. Our study clearly identified a structural feature that should be retained for good activity and also a moiety that can tolerate various modifications and, thus, is ideal for further changes.


Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.
Chronic nicotine administration increases α4β2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at α4β2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ∼150 times its affinity for α4β2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not up-regulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all α4β2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.


Manipulating Decisiveness in Decision Making: Effects of Clonidine on Hippocampal Search Strategies.
Decisiveness is the ability to commit to a decision quickly and efficiently; in contrast, indecision entails the repeated consideration of multiple alternative possibilities. In humans, the α2-adrenergic receptor agonist clonidine increases decisiveness in tasks that require planning through unknown neural mechanisms. In rats, indecision is manifested as reorienting behaviors at choice points (vicarious trial and error [VTE]), during which hippocampal representations alternate between prospective options. To determine whether the increase in decisiveness driven by clonidine also entails changes in hippocampal search processes, we compared the effect of clonidine on spatial representations in hippocampal neural ensembles as rats passed through a T-shaped decision point. Consistent with previous experiments, hippocampal representations reflected both chosen and unchosen paths during VTE events under saline control conditions. Also, consistent with previous experiments, hippocampal representations reflected the chosen path more than the unchosen path when the animal did not show VTE at the choice point. Injection of clonidine suppressed the spatial representation of the unchosen path at the choice point on VTE laps and hastened the differentiation of spatial representations of the chosen path from the unchosen path on non-VTE laps to appear before reaching the choice point. These results suggest that the decisiveness seen under clonidine is due to limited exploration of potential options in hippocampus, and suggest novel roles for noradrenaline as a modulator of the hippocampal search processes. Significance statement: Clonidine, an α2-adrenergic receptor agonist, which decreases the level of noradrenaline in vivo, has an interesting effect in humans and other animals: it makes them more decisive. However, the mechanisms by which clonidine makes them more decisive remain unknown. Researchers have speculated that clonidine limits the amount of mental search that subjects do when planning options. We test this hypothesis by measuring the mental search strategy in rats through hippocampal recordings. We find that clonidine limits the options searched by rats, suggesting that noradrenaline also plays a role in balancing exploration and exploitation in internally simulated behaviors, similar to its role in balancing exploration and exploitation in external behaviors.


Biomonitoring of children exposure to urban pollution and environmental tobacco smoke with hair analysis - A pilot study on children living in Paris and Yeu Island, France.
The impact of pollution on children's health has been increasingly pointed out in numerous studies which emphasized their increased vulnerability compared to adults. This pilot study investigated the relevance of hair analysis for the assessment of children exposure to pollution and to environmental tobacco smoke (ETS). The methodology based on GC-MS/MS and LC-MS/MS, is the first one to investigate simultaneously parent PAH (n = 15), PAH metabolites (n = 56), nicotine and cotinine in a biological matrix. The method was applied to hair samples collected from 25 children, aged from 2 to 11 years, living in Paris, France, selected as densely populated area with urban pollution including vehicle exhausts, and Yeu Island, a French island in the Atlantic ocean, selected as control area with low population density and no fuel powered vehicles. Nicotine and cotinine were detected in all the samples at concentrations up to 2275 pg/mg and 110 pg/mg respectively, suggesting exposure to ETS in the two areas. 10 parent PAH and 10 metabolites were detected in 100% and in >90% of the samples respectively. Eight of these biomarkers presented a significantly higher concentration in children from Paris than from Yeu Island. The results suggest association between PAH exposure and estimated time of exposure to vehicle exhaust as well as higher exposure to both PAH and ETS in the youngest children. Although these findings need to be confirmed on wider populations, the results obtained in this pilot study strongly support the relevance of hair analysis for the biomonitoring of children exposure to urban pollution and ETS.


Impact of user fees on attendance at a referral centre for sexually transmitted diseases in Kenya.
We investigated the impact of a short-lived policy of charging fees to patients attending public-sector outpatient health facilities in Kenya by collecting data on attendance at Nairobi's Special Treatment Clinic for sexually transmitted diseases (STDs) before (23 months), during (9 months), and after (15 months) the user-charge period. During the user-charge period, the seasonally adjusted total mean monthly attendance of men decreased significantly to 40% (95% CI 36-45) of that before fees were levied. Attendance rose in the post-user-charge period, but reached only 64% (59-68) of the pre-user-charge level. For women, the adjusted total mean monthly attendance during the user-charge period was reduced significantly to 65% (55-77) of the pre-user-charge level. Mean monthly attendance by women rose in the post-user-charge period to 22% (9-37) above the pre-user-charge level. There was no evidence of an increase in attendance over the course of the user-charge period among either men or women. The introduction of user fees probably increased the number of untreated STDs in the population, with potentially serious long-term health implications. The user-fee experience in Kenya should be carefully evaluated before similar measures are introduced elsewhere.


A Magnet-Based Timing Tystem to Detect Gate Crossings in Alpine Ski Racing.
In alpine skiing, intermediate times are usually measured with photocells. However, for practical reasons, the number of intermediate cells is limited to three⁻four, making a detailed timing analysis difficult. In this paper, we propose and validate a magnet-based timing system allowing for the measurement of intermediate times at each gate. Specially designed magnets were placed at each gate and the athletes wore small magnetometers on their lower back to measure the instantaneous magnetic field. The athlete's gate crossings caused peaks in the measured signal which could then be related to the precise instants of gate crossings. The system was validated against photocells placed at four gates of a slalom skiing course. Eight athletes skied the course twice and one run per athlete was included in the validation study. The 95% error intervals for gate-to-gate timing and section times were below 0.025 s. Each athlete's gate-to-gate times were compared to the group's average gate-to-gate times, revealing small performance differences that would otherwise be difficult to measure with a traditional photocell-based system. The system could be used to identify the effect of tactical choices and athlete specific skiing skills on performance and could allow a more efficient and athlete-specific performance analysis and feedback.


Glycosylated hemoglobin level and carotid intimal-medial thickening in nondiabetic individuals. The Atherosclerosis Risk in Communities Study.
People with diabetes are at increased risk for cardiovascular events. However, questions remain about what role, if any, homeostatic glucose control plays in the development of cardiovascular disease among nondiabetic individuals. We investigated the relationship between HbA1c level and carotid intimal-medial thickening in normoglycemic individuals. We conducted a case-control study among 208 normoglycemic individuals (fasting glucose < or = 6.4 mmol/l and no history of diabetes) who had carotid initial-medial thickening (case subjects) and 208 normoglycemic control subjects individually matched for age, sex, race, field center, and date of exam. Subjects were free-living men and women, aged 45-64 years at baseline, who participated in the Atherosclerosis Risk in Communities (ARIC) Study. HbA1c levels, expressed as percent of total hemoglobin, ranged from 4 to 7% and correlated only modestly with single measurements of fasting glucose (r = 0.16) and fasting insulin (r = 0.14). The mean level of HbA1c was 5.18% among case subjects and 5.07% among control subjects (P = 0.004, paired t test). As compared with the first quartile of HbA1c the matched relative odds of being a case were 1.15, 1.33, and 2.30 for the second, third, and fourth quartiles, respectively (P = 0.005 for linear trend). After multivariate adjustment for age, fasting glucose, fasting insulin, BMI, smoking status, hypertension, LDL cholesterol, HDL cholesterol, fibrinogen, and education level, the respective relative odds estimates were 0.98, 1.07, and 1.88 (P = 0.16 for linear trend). When modeled linearly as a continuous variable and after adjustment for the above-mentioned covariates, a 1% point increment in HbA1c level was associated with 1.77 greater odds of being a case (95% CI, 0.9-3.5). These data provide some support to the hypothesis that in the absence of diabetes, homeostatic glycemic control is a risk factor for atherosclerosis.


Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes.
Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms. To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation. The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1alpha (IL1alpha)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting. IL1alpha treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1alpha-induced expression of ADAMTS4 mRNA and protein. IL1alpha-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1alpha-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1alpha treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment. These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1alpha-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.


How proteins get in touch: interface prediction in the study of biomolecular complexes.
Protein-protein interface prediction is a booming field, with a substantial growth in the number of new methods being published the last two years. The increasing number of available three-dimensional structures of protein-protein complexes has enabled large-scale statistical analyses of protein interfaces, considering evolutionary, physicochemical and structural properties. Successful combinations of these properties have led to more accurate interface predictors in recent years. In addition to parametric combination, machine learning algorithms have become popular. In the meantime, assessing the absolute and relative performance of interface predictors remains very difficult: This is due to differences in both the output of the various interface predictors, and in the evaluation criteria used by their respective authors. This review provides an overview of the state of the art in the field, and discusses the performance of existing interface predictors. The focus is mainly on protein-protein interface prediction, although most issues are also valid for other kinds of interface prediction.


Involvement of the penta-EF-hand protein Pef1p in the Ca2+-dependent regulation of COPII subunit assembly in Saccharomyces cerevisiae.
Although it is well established that the coat protein complex II (COPII) mediates the transport of proteins and lipids from the endoplasmic reticulum (ER) to the Golgi apparatus, the regulation of the vesicular transport event and the mechanisms that act to counterbalance the vesicle flow between the ER and Golgi are poorly understood. In this study, we present data indicating that the penta-EF-hand Ca(2+)-binding protein Pef1p directly interacts with the COPII coat subunit Sec31p and regulates COPII assembly in Saccharomyces cerevisiae. ALG-2, a mammalian homolog of Pef1p, has been shown to interact with Sec31A in a Ca(2+)-dependent manner and to have a role in stabilizing the association of the Sec13/31 complex with the membrane. However, Pef1p displayed reversed Ca(2+) dependence for Sec13/31p association; only the Ca(2+)-free form of Pef1p bound to the Sec13/31p complex. In addition, the influence on COPII coat assembly also appeared to be reversed; Pef1p binding acted as a kinetic inhibitor to delay Sec13/31p recruitment. Our results provide further evidence for a linkage between Ca(2+)-dependent signaling and ER-to-Golgi trafficking, but its mechanism of action in yeast seems to be different from the mechanism reported for its mammalian homolog ALG-2.


Design principle for improved three-dimensional ac electro-osmotic pumps.
Three-dimensional (3D) ac electro-osmotic (ACEO) pumps have recently been developed that are much faster and more robust than previous planar designs. The basic idea is to create a "fluid conveyor belt" by placing opposing ACEO slip velocities at different heights. Current designs involve electrodes with electroplated steps, whose heights have been optimized in simulations and experiments. Here, we consider changing the boundary conditions-rather than the geometry-and predict that flow rates can be further doubled by fabricating 3D features with nonpolarizable materials. This amplifies the fluid conveyor belt by removing opposing flows on the vertical surfaces, and it increases the slip velocities that drive the flow.


Upregulation of the lactate transporter monocarboxylate transporter 1 at the blood-brain barrier in a rat model of attention-deficit/hyperactivity disorder suggests hyperactivity could be a form of self-treatment.
The energy deficit hypothesis of attention-deficit/hyperactivity disorder (ADHD) suggests that low lactate production by brain astrocytes causes the symptoms of the disorder. Astrocytes are the main producers of lactate in the brain; however, skeletal muscles can produce the most lactate in the body. The lactate production by skeletal muscles increases with physical activity, as does the expression of the lactate transporter monocarboxylate transporter 1 (MCT1) at the blood-brain barrier (BBB). We hypothesise that children with ADHD, by being hyperactive, increase lactate production by skeletal muscles and transport it into the brain to compensate for low supply by astrocytes. The aim of this study was to explore whether the level of MCT1 is altered in the brain in an animal model of ADHD. The MCT1 expression was quantified on hippocampal brain sections from the best available rat model of ADHD, i.e., the spontaneously hypertensive rat (SHR) (n = 12), and the relevant control, the Wistar Kyoto rat (WKY) (n = 12), by the use of quantitative immunofluorescence laser scanning microscopy and postembedding immunogold electron microscopy. The results revealed significantly higher levels of hippocampal MCT1 immunoreactivity in SHR compared to WKY, particularly at the BBB. These results indicate that lactate flux through MCT1 between the body and the brain could be upregulated in children with ADHD. This study adds to previous research suggesting hyperactivity may be beneficial in ADHD; Children with ADHD possibly display a hyperactive behaviour in order to raise skeletal muscle lactate production, MCT1 expression and flux over the BBB to supply the brain with lactate.


Light trapping in ultrathin silicon photonic crystal superlattices with randomly-textured dielectric incouplers.
We report here several different superlattice photonic crystal based designs for 200nm thick c-Si solar cells, demonstrating that these structures have the ability to increase broadband absorption from λ = 300nm to 1100nm by more than 100% compared to a planar cell with an optimized anti-reflection coating. We show that adding superlattices into photonic crystals introduces new optical modes that contribute to enhanced absorption. The greatest improvements are obtained when combining a superlattice photonic crystal with a randomly textured dielectric coating that improves incoupling into the modes of the absorbing region. Finally, we show that our design methodology is also applicable to layers 1 to 4 microns in thickness, where absorbed currents competitive with conventional thick Si solar cells may be achieved.


Computational modeling of growth: systemic and pulmonary hypertension in the heart.
We introduce a novel constitutive model for growing soft biological tissue and study its performance in two characteristic cases of mechanically induced wall thickening of the heart. We adopt the concept of an incompatible growth configuration introducing the multiplicative decomposition of the deformation gradient into an elastic and a growth part. The key feature of the model is the definition of the evolution equation for the growth tensor which we motivate by pressure-overload-induced sarcomerogenesis. In response to the deposition of sarcomere units on the molecular level, the individual heart muscle cells increase in diameter, and the wall of the heart becomes progressively thicker. We present the underlying constitutive equations and their algorithmic implementation within an implicit nonlinear finite element framework. To demonstrate the features of the proposed approach, we study two classical growth phenomena in the heart: left and right ventricular wall thickening in response to systemic and pulmonary hypertension.


Clinical presentation and surgical management of invasive lobular carcinoma of the breast.
Invasive lobular carcinoma is the second most common histological type of breast cancer and differs from invasive ductal carcinoma also in some clinical features. Multifocal or multicentric as well as contralateral diseases are more frequently found among patients with lobular carcinoma. Tumor size at diagnosis is larger than in patients with ductal carcinoma due to diagnostic challenges associated with lobular histology. For surgical management, breast conserving surgery followed by radiotherapy offers equal local control as mastectomy. Controversy however exists regarding risk for positive margins and subsequent need for second operations. Axillary staging can be safely performed by sentinel node biopsy if lymph nodes are clinically negative, even in multifocal or multicentric disease.


Levels of naturally occurring gamma radiation measured in British homes and their prediction in particular residences.
Gamma radiation from natural sources (including directly ionising cosmic rays) is an important component of background radiation. In the present paper, indoor measurements of naturally occurring gamma rays that were undertaken as part of the UK Childhood Cancer Study are summarised, and it is shown that these are broadly compatible with an earlier UK National Survey. The distribution of indoor gamma-ray dose rates in Great Britain is approximately normal with mean 96 nGy/h and standard deviation 23 nGy/h. Directly ionising cosmic rays contribute about one-third of the total. The expanded dataset allows a more detailed description than previously of indoor gamma-ray exposures and in particular their geographical variation. Various strategies for predicting indoor natural background gamma-ray dose rates were explored. In the first of these, a geostatistical model was fitted, which assumes an underlying geologically determined spatial variation, superimposed on which is a Gaussian stochastic process with Matérn correlation structure that models the observed tendency of dose rates in neighbouring houses to correlate. In the second approach, a number of dose-rate interpolation measures were first derived, based on averages over geologically or administratively defined areas or using distance-weighted averages of measurements at nearest-neighbour points. Linear regression was then used to derive an optimal linear combination of these interpolation measures. The predictive performances of the two models were compared via cross-validation, using a randomly selected 70 % of the data to fit the models and the remaining 30 % to test them. The mean square error (MSE) of the linear-regression model was lower than that of the Gaussian-Matérn model (MSE 378 and 411, respectively). The predictive performance of the two candidate models was also evaluated via simulation; the OLS model performs significantly better than the Gaussian-Matérn model.


Insulin sensitivity as a mediator of the relationship between BMI and working memory-related brain activation.
Midlife obesity is associated with cognitive deficits and cerebral atrophy in older age. However, little is known about the early signs of these deleterious brain effects or the physiological mechanisms that underlie them. Functional magnetic resonance imaging (fMRI) allows us to detect early changes in brain response to cognitive challenges while behavioral performance is still intact. Accordingly, we examined the impact of obesity on functional activation during a 2-Back task in 32 cognitively normal middle-aged adults, who were classified into normal, overweight, and obese groups according to BMI. Additionally, we examined insulin sensitivity as a potential mediator of the relationship between BMI and brain activation. Insulin sensitivity is of special interest because insulin is strongly associated with both obesity and central nervous system functioning. Group differences in task-related brain activation were examined in a priori regions of interest (ROIs) using ANOVA. The obese BMI group displayed significantly lower task-related activation in the right parietal cortex, BA 40/7, (F(2,29) = 5.26, P = 0.011) than the normal (P = 0.016) and overweight (P = 0.047) BMI groups. Linear regression and bootstrapping methods for assessing indirect effects indicated that insulin sensitivity fully mediated the relationship between task-related activation in the right parietal cortex and BMI ((F(3,28) = 9.03, P = 0.000), β = 0.611, P = 0.001, 95% confidence interval: -2.548 to -0.468). In conclusion, obesity in middle age was related to alterations in brain activation during a cognitive challenge and this association appeared to be mediated by insulin sensitivity.


Evoked brain responses are generated by feedback loops.
Neuronal responses to stimuli, measured electrophysiologically, unfold over several hundred milliseconds. Typically, they show characteristic waveforms with early and late components. It is thought that early or exogenous components reflect a perturbation of neuronal dynamics by sensory input bottom-up processing. Conversely, later, endogenous components have been ascribed to recurrent dynamics among hierarchically disposed cortical processing levels, top-down effects. Here, we show that evoked brain responses are generated by recurrent dynamics in cortical networks, and late components of event-related responses are mediated by backward connections. This evidence is furnished by dynamic causal modeling of mismatch responses, elicited in an oddball paradigm. We used the evidence for models with and without backward connections to assess their likelihood as a function of peristimulus time and show that backward connections are necessary to explain late components. Furthermore, we were able to quantify the contribution of backward connections to evoked responses and to source activity, again as a function of peristimulus time. These results link a generic feature of brain responses to changes in the sensorium and a key architectural component of functional anatomy; namely, backward connections are necessary for recurrent interactions among levels of cortical hierarchies. This is the theoretical cornerstone of most modern theories of perceptual inference and learning.


Risk communication related to animal products derived from biotechnology.
Previous chapters of this review have dealt with the key considerations related to the application of biotechnology in veterinary science and animal production. This article explores the theory and practice of risk communication and sets out the basic principles for good risk communication when dealing with new technologies, uncertainty, and cautious and sceptical consumers. After failure to communicate with consumers and stakeholders about the risk to human health from bovine spongiform encephalopathy (BSE) in the 1990s, Government Agencies in the United Kingdom have made significant improvements in risk communication. The official inquiry that followed the BSE crisis concluded that a policy of openness was the correct approach, and this article emphasises the importance of consultation, consistency and transparency. There are, however, many different factors that affect public perception of risk (religious, political, social, cultural, etc.) and developing effective risk communication strategies must take all of these complex issues into consideration.


Preliminary Investigation of Civilian Clinician Perspectives & Just-in-Time Guidance for Tourniquet Use to "Stop the Bleed".
The American College of Surgeons (ACS) encourages clinicians to provide training to laypeople on tourniquet application. It is unclear whether clinicians are confident in their abilities and equipped with adequate knowledge, skills, and resources. This study aimed to determine surgical trainee knowledge and attitudes regarding tourniquet application and compare the effectiveness of instructions. Thirty surgical trainees performed a tourniquet application simulation using a Combat Application Tourniquet and one of the three instructions sets developed by ACS, Department of Homeland Security, and the tourniquet manufacturer. Participants reported tourniquet knowledge, attitudes, and confidence and discussed the instructions. One instruction set was updated and compared to the original set with 20 new trainees. Participants with ACS instructions passed the greatest number of steps (p < 0.01) and completed the task significantly faster compared to those with manufacturer instructions (p < 0.01). Participants (80%) reported favorable views toward tourniquets but 30-60% did not align with to ACS tourniquet guidelines. Focus group participants suggested revisions to the ACS instructions. Comparing the original and revised version of these instructions resulted in no significant improvements. ACS instructions provide guidance; however, improvements to tourniquet instruction are needed for success in controlling exsanguinating hemorrhage.


Reducing eating disorder risk factors: a controlled investigation of a blended task-shifting/train-the-trainer approach to dissemination and implementation.
Recent advances in psychological intervention research have led to an increase in evidence-based interventions (EBIs), yet there remains a lag in dissemination and implementation of EBIs. Task-shifting and the train-the-trainer (TTT) model offer two potential strategies for enhancing reach of EBIs. The Body Project, an EBI found to prevent onset of eating disorders, served as the vehicle for this dissemination/implementation study. The primary aim of this study was to determine if training of peer-leaders for the Body Project could be task-shifted to undergraduate students using a hybrid task-shifting/TTT model. Our secondary aim was to determine if subgroups of participants evidenced different trajectories of change through 14-month follow-up. Regarding the first aim, we found almost no evidence to suggest that a presence of a doctoral-level trainer yielded superior participant outcomes compared to training by undergraduates alone. Regarding Aim 2, almost all classes for all variables evidenced improvement or a benign response. Additionally, for three key risk factors (thin-ideal internalization, body dissatisfaction, and ED symptoms) virtually all trajectories showed improvement. This study provides initial support for the use of a blended task-shifting/TTT approach to dissemination and implementation within prevention generally, and further support for broad dissemination of the Body Project specifically.


Low vitamin a intake affects milk iron level and iron transporters in rat mammary gland and liver.
Marginal vitamin A deficiency is common and can result in a secondary iron (Fe) deficiency. A positive correlation between maternal Fe status and milk Fe was observed in lactating women supplemented with both vitamin A and Fe but not with Fe alone, suggesting effects of vitamin A on mammary gland Fe transport. We hypothesized that low vitamin A intake during lactation elicits differential effects on mammary gland and liver Fe transport and storage proteins, thus affecting milk Fe concentration but not maternal Fe status. We fed rats a control (CON, 4 RE/g) or a marginal vitamin A diet (AD, 0.4 RE/g) through midlactation. Effects on plasma, milk, liver and mammary gland Fe and vitamin A concentrations, and divalent metal transporter-1 (DMT1), ferroportin (FPN), ferritin (Ft), and transferrin receptor (TfR) expression were determined. Dams fed AD were not vitamin A or Fe deficient. Milk and liver vitamin A and Fe and mammary gland Fe concentrations were lower in rats fed AD compared with rats fed CON. Liver TfR expression was higher, whereas mammary gland TfR expression was lower in rats fed AD compared with rats fed CON. Liver Ft was unaffected, whereas mammary gland Ft was lower in rats fed AD compared with rats fed CON. Liver and mammary gland DMT1 and FPN protein levels were lower in rats fed AD compared with rats fed CON. Our results indicate that the mammary gland and liver respond differently to marginal vitamin A intake during lactation and that milk Fe is significantly decreased due to effects on mammary gland Fe transporters, putting the nursing offspring at risk for Fe deficiency.


Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation.
The circadian clock orchestrates temporal patterns of physiology and behavior relative to the environmental light:dark cycle by generating and organizing transcriptional and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate the physiology and function of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation; a process that has been linked to pathologic inflammatory states associated with metabolic, hepatic, cardiovascular and neurodegenerative diseases - many of which are commonly reported in shift workers. Here we report, for the first time, that circadian disorganization, using independent genetic and environmental strategies, increases permeability of the intestinal epithelial barrier (i.e., gut leakiness) in mice. Utilizing chronic alcohol consumption as a well-established model of induced intestinal hyperpermeability, we also found that both genetic and environmental circadian disruption promote alcohol-induced gut leakiness, endotoxemia and steatohepatitis, possibly through a mechanism involving the tight junction protein occludin. Circadian organization thus appears critical for the maintenance of intestinal barrier integrity, especially in the context of injurious agents, such as alcohol. Circadian disruption may therefore represent a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease, as well as other conditions associated with intestinal hyperpermeability and an endotoxin-triggered inflammatory state.


Malignant pleural effusions: recent advances and ambulatory sclerotherapy.
Malignant pleural effusions are a common problem in cancer patients with advanced disease. Patients typically present with progressive dyspnea, cough, and/or chest pain that significantly compromises their quality of life. Treatment is often palliative, usually consisting of sequential thoracenteses or tube thoracostomy with or without sclerotherapy. The traditional method of treatment--tube thoracostomy with large-bore chest tubes connected to continuous wall suction--requires hospitalization, is expensive, limits patient mobility, and can cause significant patient discomfort. More recent trials have explored new techniques, including thoracoscopic insufflation of talc and small-bore catheters. Most of these studies have been performed on inpatients, although a recent multi-institutional trial was initiated to evaluate the feasibility and efficacy of ambulatory (outpatient) pleural drainage and sclerotherapy using small-bore catheters. All patients fulfilling eligibility criteria had a small-bore catheter placed in the pleural space that was then connected to a closed gravity drainage bag system. When daily tube drainage was <100 mL, sclerotherapy was performed. Response rates at our institution demonstrated 10 patients (53%) had a complete response, 5 (26%) had a partial response, and 4 (21%) had progressive disease at 30-day follow-up. These preliminary results suggest ambulatory sclerotherapy is a safe, viable alternative to conventional inpatient treatment of malignant pleural effusions in a select group of patients.


OX40 is differentially expressed on activated rat and mouse T cells and is the sole receptor for the OX40 ligand.
OX40, a member of the tumor necrosis factor (TNF) receptor/nerve growth factor (NGF) receptor superfamily was first identified as a marker of activated rat CD4+ cells with the MRC OX40 monoclonal antibody (mAb). A ligand for OX40 (called OX40 ligand or OX40L) has recently been identified and has sequence similarity to TNF. Mouse OX40L-immunoglobulin fusion protein (OX40L-Ig) binds to activated mouse CD4+ and CD8+ cells (Baum, P. R. et al., EMBO J. 1994. 13: 3992) suggesting that OX40 could have a differential pattern of expression on mouse and rat T cells. This, however, did not rule out the presence of an alternative receptor on CD8+ cells that also binds the OX40L. We have compared the binding of the MRC OX40 mAb with that of OX40L-Ig to activated rat lymph node cells and show that both recognize the same protein, namely OX40 which is expressed on CD4+ and CD4+ CD8 alpha+ cells, but not on CD4-CD8+ cells. We have raised a new mAb (MRC OX86) using recombinant mouse OX40 protein and show by two-color flow cytometry that mouse OX40 is expressed on CD4 and CD8 single-positive cells. In addition, the new MRC OX86 mAb, unlike the MRC OX40 mAb, did not block binding of the OX40L. We conclude that OX40 is differentially expressed on activated mouse and rat T cells and is the sole receptor for the OX40L.


Comparing the benefits of screening for breast cancer and lung cancer using a novel natural history model.
To estimate the impact of early detection of cancer, knowledge of how quickly primary tumors grow and at what size they shed lethal metastases is critical. We developed a natural history model of cancer to estimate the probability of disease-specific cure as a function of tumor size, the tumor volume doubling time (TVDT), and disease-specific mortality reduction achievable by screening. The model was applied to non-small-cell lung carcinoma (NSCLC) and invasive ductal carcinoma (IDC), separately. Model parameter estimates were based on Surveillance Epidemiology and End Results (SEER) cancer registry datasets and validated on screening trials. Compared to IDC, NSCLC is estimated to have a lower probability of disease-specific cure at the same detected tumor size, shed lethal metastases at smaller sizes (median: 19 mm for IDC versus 8 mm for NSCLC), have a TVDT that is almost half as long (median: 252 days for IDC versus 134 days for NSCLC). Consequently, NSCLC is associated with a lower mortality reduction from screening at the same screen detection threshold and screening interval. In summary, using a similar natural history model of cancer, we quantify the disease-specific curability attributable to screening for breast cancer, and separately lung cancer, in terms of the TVDT and onset of lethal metastases.


The effect of bone quality on the stability of ankle arthrodesis. A finite element study.
Despite uniform operating techniques, lack of fusion still occurs after ankle arthrodesis. Differences in the biological healing potential may be a factor but the mechanical performance of the arthrodesis construct because of varying bone quality also may be important. Internal compression techniques are preferred because of higher union rates, shorter fusion times, and fewer complications. A three-screw configuration has been shown to be more stable than a two-screw configuration, but it is not obvious when it should be used. Three-dimensional finite element models of intact and flat-cut ankle arthrodeses were built, using two and three screws in different configurations. Poor bone quality was simulated by decreasing Young's modulus of the bone. The constructs were loaded in torsion and dorsiflexion, and micromotions at the fusion site were measured. Bone quality had a marked effect on the stability at the arthrodesis site. Inserting two screws at 30 degrees relative to the longitudinal axis of the tibia in an intact arthrodesis seemed the best option, especially as bone quality worsened. The addition of a third screw increased the stability at the arthrodesis site. Overall, intact joint surfaces and three-screw fixation, with the lateral and medial screws inserted produced the most stable arthrodesis constructs when bone quality was poor. CLINICAL RELEVANCE. Ankle arthrodeses are technically demanding because of the shape and small size of the talus. Preoperative planning is an absolute necessity to determine placement and number of screws. This study shows that poor bone quality decreases the stability of the arthrodesis constructs, suggesting that an attempt should be made to create the most stable three-screw configuration. Finite element models can be used as an effective preoperative tool for planning screw number and placement.


A case-control study of nonrandom distribution of bleomycin-induced chromatid breaks in lymphocytes of lung cancer cases.
We used a case-control study design to determine the association between bleomycin-induced chromatid breaks and the risk of lung cancer in general and by specific histopathological types. Lymphocytes from primary blood cultures of 78 controls and 75 cases with 4 histopathological types of lung cancer were treated with 0.03 unit/ml bleomycin for 5 h, and the frequency of induced chromatid breakage and the locations of the breaks were determined in Q-banded preparations. After adjustment for their length, the larger chromosomes had more breaks than the smaller chromosomes in both cases and controls. The cases had significantly more breaks on chromosomes 4 and 5 than the controls did, with odds ratios (ORs) of 4.9 [95% confidence limits (CL), 2.0, 11.7] and 3.9 (95% CL, 1.6, 9.3), respectively. When the lung cancers were classified by histopathological type, adenocarcinomas had significantly more breaks on chromosomes 4 and 5, with ORs of 3.0 (95% CL, 1.0, 8.7) and 3.5 (95% CL, 1.2, 10.7), respectively. For squamous cell carcinoma, the ORs were significantly elevated for breaks on chromosomes 2, 4, and 5 with ORs of 3.5 (95% CL, 1.0, 11.7), 10.2 (95% CL, 2.5, 41.9), and 7.9 (95% CL, 1.9, 32.8). For small cell carcinoma, breaks on chromosomes 2 and 4 showed significantly increased ORs of 33.2 (95% CL, 2.2, 513.3) and 20.4 (95% CL, 1.7, 250.1), respectively. However, no specific chromatid breaks were detected in cases with large cell carcinoma. When the frequency of chromatid breaks at specific regions was calculated, breaks at 4p14, 4q27, 4q31, 5q21-q22, 5q31, and 5q33 were significantly more common in lung cancer cases than in controls. Lung cancer risk had a dose-response relationship with breaks on chromosomes 4 and 5. Cigarette smoking had a strong interaction with breaks on chromosomes 2, 4, and 5. The findings suggest that the susceptibility of particular chromosome loci to mutagenic damage may be a risk factor for specific types of lung cancer.


International population movements and regional Plasmodium falciparum malaria elimination strategies.
Calls for the eradication of malaria require the development of global and regional strategies based on a strong and consistent evidence base. Evidence from the previous global malaria eradication program and more recent transborder control campaigns have shown the importance of accounting for human movement in introducing infections to areas targeted for elimination. Here, census-based migration data were analyzed with network analysis tools, Plasmodium falciparum malaria transmission maps, and global population databases to map globally communities of countries linked by relatively high levels of infection movements. The likely principal sources and destinations of imported cases in each region were also mapped. Results indicate that certain groups of countries, such as those in West Africa and central Asia are much more strongly connected by relatively high levels of population and infection movement than others. In contrast, countries such as Ethiopia and Myanmar display significantly greater isolation in terms of likely infection movements in and out. The mapping here of both communities of countries linked by likely higher levels of infection movement, and "natural" migration boundaries that display reduced movement of people and infections between regions has practical utility. These maps can inform the design of malaria elimination strategies by identifying regional communities of countries afforded protection from recolonization by surrounding regions of reduced migration. For more isolated countries, a nationally focused control or elimination program is likely to stand a better chance of success than those receiving high levels of visitors and migrants from high-transmission regions.


Outcome of wheeze in childhood: the influence of atopy.
We have previously demonstrated that the adult outcome of childhood asthma differs from that of wheeze occurring only in the presence of infection. This paper examines the role of atopy in relation to outcome. We investigated the atopic status, current symptoms and bronchial reactivity to methacholine of 235 subjects aged 34-40 yrs, originally classified at age 10-15 yrs as having asthma (asthma group), wheeze only in the presence of infection (wheezy group), or no respiratory symptoms (comparison group). Subjects from the original asthma group were more likely to be atopic as defined by skin test reactivity, total serum immunoglobulin E (IgE) measurement or specific IgE radio allergosorbent test (RAST) measurement than those from the wheezy group. The wheezy group differed significantly from the reference group only in RAST results, when other variables were taken into account. In a logistic regression model, the important independent predictors for adult wheezing symptoms were original group, atopy and current smoking. Methacholine responsiveness was independently associated with original group (the asthma group were more likely to respond positively), atopy and female gender. The results suggest that atopy is an important predictor for wheeze and bronchial hyperreactivity in middle age. However, the difference in outcome for children who had asthma compared to those who had wheeze only in the presence of infection cannot be explained by atopy alone.


Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species.
Epidemiological evidence demonstrates positive correlation between environmental and occupational arsenic or fluoride exposure and risk to various cardio-respiratory disorders. Arsenic-exposure has been associated with atherosclerosis, hypertension, cerebrovascular diseases, ischemic heart disease, and peripheral vascular disorders, whereas Fluoride-exposure manifests cardiac irregularities and low blood pressure (BP). Present study aims to study the combined effects of these toxicants on various cardio-respiratory variables in male rats. Single intravenous (i.v.) dose of arsenic (1, 5, 10 mg/kg) or fluoride (5, 10, 20, 36.5 mg/kg) either alone or in combination were administered. Individual exposure to arsenic or fluoride led to a significant depletion of mean arterial pressure, heart rate (HR), respiration rate and neuromuscular (NM) transmission in a dose-dependent manner. These changes were accompanied by increased levels of blood reactive oxygen species (ROS) and decreased glutathione (GSH) concentrations. An increase in the blood acetyl cholinesterase (AChE) activity was observed in both arsenic or fluoride exposed rats. These changes were significantly more pronounced in arsenic-exposed animals than in fluoride. During combined exposure to arsenic (5 mg/kg) + fluoride (20 mg/kg) or arsenic (10 mg/kg) + fluoride (36.5 mg/kg) the toxic effects were more pronounced compared to individual toxicities of arsenic or fluoride alone. However, combined exposure to arsenic (5 mg/kg) + fluoride (36.5 mg/kg) resulted in antagonistic effects on variables suggestive of altered cardio-respiratory function and oxidative stress. The results from the present study suggest that arsenic or fluoride individually demonstrate cardio-respiratory failure at all doses whereas during combination exposure these toxins show variable toxicities; both synergistic and antagonistic effects depending upon the dose. Moreover, it may be concluded that arsenic and/or fluoride cardio-respiratory toxicity may be mediated via oxidative stress. However, these results are new in the discipline thus requires further exploration.


Role of the peripheral chemoreflex in the early stages of ventilatory acclimatization to altitude.
This review of ventilatory acclimatization to altitude/hypoxia (VAH) emphasizes the widely differing timescales that VAH is considered to encompass. The review concludes: (1) that early (24-48h) VAH is unlikely to arise as a reaction to the respiratory alkalosis that is normally associated with exposure to hypoxia; (2) that changes in peripheral chemoreflex function may be sufficiently rapid to explain early VAH; (3) that alterations in gene expression induced by hypoxia through the hypoxia-inducible factor (HIF) signalling pathway may underlie a major component of VAH; and (4) that compensatory adjustments to acid-base balance in response to the initial respiratory alkalosis may have more significance for the slower changes observed later in VAH.


The evolution of cognitive-behavioral therapy for psychosis.
Cognitive therapy for psychosis has developed over the past 30 years from initial case studies, treatment manuals, pilot randomized controlled studies to fully powered and methodologically rigorous efficacy and, subsequently, effectiveness trials. Reviews and meta-analyses have confirmed the benefits of the interventions. Considered appraisal by government and professional organizations has now led to its inclusion in international treatment guidelines for schizophrenia. Patients consistently ask for access to psychotherapeutic interventions, and it is slowly becoming available in many European countries and other parts of the world, eg, US and the People's Republic of China. However, it remains unacceptably difficult to access for the vast majority of people with psychosis who could benefit from it. Psychosis affects people in the prime of their lives and leads to major effects on their levels of distress, well-being, and functioning, and also results in major costs to society. Providing effective interventions at an early stage has the potential to reduce the high relapse rates that occur after recovery from first episode and the ensuing morbidity and premature mortality associated with psychosis.


Apolipoprotein-E deficiency results in an altered stress responsiveness in addition to an impaired spatial memory in young mice.
It has been suggested that Alzheimer's disease (AD) is associated with an altered neurotrophic function of apolipoprotein-E (ApoE) and abnormal neuroendocrine activities. In the present study we investigated stress responsiveness of ApoE-deficient mice. Firstly, two sessions of restraint were introduced, 20 min per day for two (session 1) and three (session 2) consecutive days. In session 1, there was no difference between genotypes in open-field activity in response to restraint stress. In session 2, spatial memory was assessed in a Morris Water Maze 'Place Learning Set' task immediately following stress. Restraint stress caused a significant impairment of spatial memory in wild-type mice. The non-restraint ApoE-deficient mice showed a severe impairment of spatial memory similar to that of the restrained wild-type mice. Restraint stress had no obvious effect on spatial memory in ApoE-deficient mice until the third day of testing, when there was a decrease in reference memory compared with their non-restraint controls. In addition, the first session of restraint stress had an inhibitory effect on food intake in wild-type but not ApoE-deficient mice, and a longer-lasting effect on body weight in the wild-type than ApoE-deficient mice. ApoE-deficient mice showed a weaker corticosterone response to the initial restraint stress and a slower descending rate in serum corticosterone level during a 30-min post-stress period than their wild-type controls. However, higher baseline levels and stronger corticosterone responses were observed in ApoE-deficient mice than in wild-type mice when exposed to repeated restraint stress. The expression of ApoE mRNA was upregulated in the hypothalamus in wild-type mice exposed to repeated restraint stress. Taken together, these results demonstrate that ApoE deficiency causes a memory impairment and an altered stress responsiveness in mice.


Analysis of HIV-1 envelope evolution suggests antibody-mediated selection of common epitopes among Chinese former plasma donors from a narrow-source outbreak.
The HIV-1 envelope mutates rapidly to evade recognition and killing, and is a major target of humoral immune responses and vaccine development. Identification of common epitopes for vaccine development have been complicated by genetic variation on both virus and host levels. We studied HIV-1 envelope gp120 evolution in 12 Chinese former plasma donors infected with a purportedly single founder virus, with the aim of identifying common antibody epitopes under immune selection. We found five amino acid sites under significant positive selection in ≥50% of the study participants, and 22 sites consistent with antibody-mediated selection. Despite strong selection pressure, some sites housed a limited repertoire of amino acids. Structural modelling revealed that most of the variable amino acid sites were located on the exposed distal edge of the Gp120 trimer, whilst invariant sites clustered within the centre of the protein complex. Two sites, flanking the V3 hypervariable loop, represent novel antibody sites. Analysis of HIV-1 evolution in hosts infected with a narrow-source virus may provide insight and novel understanding of common epitopes under antibody-mediated selection. If verified in functional studies, such epitopes could be suitable as targets in vaccine development.


Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.
Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.


The Fasting Hyperglycaemia Study: II. Randomized controlled trial of reinforced healthy-living advice in subjects with increased but not diabetic fasting plasma glucose.
Self-referred subjects (N = 227) thought to be at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) and with fasting plasma glucose (FPG) in the range of 5.5 to 7.7 mmol.L-1 on two consecutive tests 2 weeks apart were randomized to reinforced or basic healthy-living advice. They were simultaneously allocated either to a sulfonylurea group or a control group in a two-by-two factorial design. A total of 201 subjects in three English and two French centers completed 1 year's follow-up study. Reinforced advice recommending dietary modification and increased exercise was given every 3 months, and basic advice was given once at the initial visit. Glycemia was monitored by FPG, dietary compliance by body weight and food diaries, and fitness compliance by bicycle ergometer assessment and exercise diaries. Both reinforced and basic advice groups had a significant mean reduction in body weight (1.5 kg) at 3 months, although the weight subsequently returned to baseline. After 1 year, subjects allocated to reinforced advice versus basic advice (1) reported a lower fat intake (34.1% v 35.8%, P = .04) with no difference in lipid profiles, (2) had improved fitness as shown by increased calculated maximal oxygen uptake ([Vo2max] 2.39 v 2.18 L.min-1, P = .007) with no change in insulin sensitivity, (3) showed no change in FPG, glucose tolerance, or hemoglobin A1c (HbA1c), and (4) showed a greater tendency to withdraw from the study (16% v 7%, P = .03). In conclusion, reinforced healthy-living advice given to self-referred subjects with increased FPG did not encourage sufficiently pronounced life-style changes for significantly greater effects on body weight and glycemia in a 1-year study than basic healthy-living advice.


HOME Plus: Program design and implementation of a family-focused, community-based intervention to promote the frequency and healthfulness of family meals, reduce children's sedentary behavior, and prevent obesity.
Involvement in meal preparation and eating meals with one's family are associated with better dietary quality and healthy body weight for youth. Given the poor dietary quality of many youth, potential benefits of family meals for better nutritional intake and great variation in family meals, development and evaluation of interventions aimed at improving and increasing family meals are needed. This paper presents the design of key intervention components and process evaluation of a community-based program (Healthy Home Offerings via the Mealtime Environment (HOME) Plus) to prevent obesity. The HOME Plus intervention was part of a two-arm (intervention versus attention-only control) randomized-controlled trial. Ten monthly, two-hour sessions and five motivational/goal-setting telephone calls to promote healthy eating and increasing family meals were delivered in community-based settings in the Minneapolis/St. Paul, MN metropolitan area. The present study included 81 families (8-12 year old children and their parents) in the intervention condition. Process surveys were administered at the end of each intervention session and at a home visit after the intervention period. Chi-squares and t-tests were used for process survey analysis. The HOME Plus program was successfully implemented and families were highly satisfied. Parents and children reported that the most enjoyable component was cooking with their families, learning how to eat more healthfully, and trying new recipes/foods and cooking tips. Average session attendance across the ten months was high for families (68%) and more than half completed their home activities. Findings support the value of a community-based, family-focused intervention program to promote family meals, limit screen time, and prevent obesity. NCT01538615.


Developmental Maturation of the Precuneus as a Functional Core of the Default Mode Network.
Efforts to map the functional architecture of the developing human brain have shown that connectivity between and within functional neural networks changes from childhood to adulthood. Although prior work has established that the adult precuneus distinctively modifies its connectivity during task versus rest states [Utevsky, A. V., Smith, D. V., & Huettel, S. A. Precuneus is a functional core of the default-mode network. Journal of Neuroscience, 34, 932-940, 2014], it remains unknown how these connectivity patterns emerge over development. Here, we use fMRI data collected at two longitudinal time points from over 250 participants between the ages of 8 and 26 years engaging in two cognitive tasks and a resting-state scan. By applying independent component analysis to both task and rest data, we identified three canonical networks of interest-the rest-based default mode network and the task-based left and right frontoparietal networks (LFPN and RFPN, respectively)-which we explored for developmental changes using dual regression analyses. We found systematic state-dependent functional connectivity in the precuneus, such that engaging in a task (compared with rest) resulted in greater precuneus-LFPN and precuneus-RFPN connectivity, whereas being at rest (compared with task) resulted in greater precuneus-default mode network connectivity. These cross-sectional results replicated across both tasks and at both developmental time points. Finally, we used longitudinal mixed models to show that the degree to which precuneus distinguishes between task and rest states increases with age, due to age-related increasing segregation between precuneus and LFPN at rest. Our results highlight the distinct role of the precuneus in tracking processing state, in a manner that is both present throughout and strengthened across development.


Evaluating physiological dynamics via synchrosqueezing: prediction of ventilator weaning.
Oscillatory phenomena abound in many types of signals. Identifying the individual oscillatory components that constitute an observed biological signal leads to profound understanding about the biological system. The instantaneous frequency (IF), the amplitude modulation (AM), and their temporal variability are widely used to describe these oscillatory phenomena. In addition, the shape of the oscillatory pattern, repeated in time for an oscillatory component, is also an important characteristic that can be parametrized appropriately. These parameters can be viewed as phenomenological surrogates for the hidden dynamics of the biological system. To estimate jointly the IF, AM, and shape, this paper applies a novel and robust time-frequency analysis tool, referred to as the synchrosqueezing transform (SST). The usefulness of the model and SST are shown directly in predicting the clinical outcome of ventilator weaning. Compared with traditional respiration parameters, the breath-to-breath variability has been reported to be a better predictor of the outcome of the weaning procedure. So far, however, all these indices normally require at least 20 min of data acquisition to ensure predictive power. Moreover, the robustness of these indices to the inevitable noise is rarely discussed. We find that based on the proposed model, SST and only 3 min of respiration data, the ROC area under curve of the prediction accuracy is 0.76. The high predictive power that is achieved in the weaning problem, despite a shorter evaluation period, and the stability to noise suggest that other similar kinds of signal may likewise benefit from the proposed model and SST.


Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of Shanghai women and men.
Exposure to certain phenols is ubiquitous because of their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations. We sought to identify predictors of exposure and to assess the reproducibility of phenol concentrations across serial spot urine samples among Chinese adults. We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997-2006 from 50 participants of the Shanghai Women's Health Study cohort and during 2002-2006 from 50 participants of the Shanghai Men's Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test, and assessed reproducibility among serial samples using intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs). Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who had taken medicine within the previous 24 hr had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC = 0.54-0.60, SCC = 0.43-0.56), but lower for other analytes (ICC = 0.20-0.29). Reproducibility among women was low (ICC = 0.13-0.39), but increased when restricted to morning-only urine samples. Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women.


Response Assessment Criteria and Their Applications in Lymphoma: Part 2.
Interim and end-of-treatment PET/CT have become central to the evaluation of Hodgkin and non-Hodgkin lymphoma. This review article seeks to aid clinical decision making by providing an overview of available data on the diagnostic and prognostic value of PET/CT imaging for response assessment and pretransplant evaluation in lymphoma. The relative strengths and limitations of these techniques in various disease subtypes and clinical scenarios are explored, along with their current standards for reporting and latest developments. Particular attention is given to response-adapted therapy, which is emerging as a cornerstone of clinical management.


Characterization of the operon encoding the YpkA Ser/Thr protein kinase and the YopJ protein of Yersinia pseudotuberculosis.
The Ser/Thr protein kinase YpkA, encoded by the virulence plasmid pIB1, is an indispensable virulence determinant of Yersinia pseudotuberculosis [E. E. Galyov, S. Håkansson, A. Forsberg, and H. Wolf-Watz, Nature (London) 361:730-732, 1993]. In this study, the organization of the ypkA-containing operon and the in vitro regulation of this transcriptional unit were characterized. The operon contains two structural genes, ypkA and yopJ, and is regulated by temperature and the extracellular concentration of Ca2+, as are the yop genes. The two proteins were secreted without posttranslational processing, showing that YpkA and YopJ belong to the Yop family. Mutational analysis revealed that, in contrast to all other Yop proteins so far studied, the YopJ protein was dispensable for virulence of Y. pseudotuberculosis.


Progressive and lasting amplification of accumbal nicotine-seeking neural signals.
Although neuroadaptations in the nucleus accumbens (NAc) are thought to contribute to nicotine addiction, little is known about the chronic effects of nicotine on NAc neuronal activity. In the present experiment, rats were exposed to a 23 d period of nicotine self-administration (SA), a 30 d abstinence period, and a 7 d period of reexposure to SA. Chronic electrophysiological procedures were used to record the activity of individual NAc neurons on the 3rd and 23rd days of initial SA and on the 1st, 3rd, and 7th days of reexposure. Between-session comparisons showed that NAc neurons exhibit two patterns of plasticity under the present experimental conditions. First, phasic-increase firing patterns time-locked to the nicotine-reinforced lever press do not change during initial SA, but then show increases in prevalence and amplitude after abstinence, which persist during reexposure. Second, for neurons that show no phasic response time-locked to the nicotine-reinforced lever press, average baseline and SA firing rates decrease during initial SA, return to normal during abstinence, and decrease again during reexposure. As a combined consequence of the two types of neurophysiological plasticity, average firing rate of NAc neurons at the time of nicotine-directed behavior undergoes a progressive and persistent net amplification, across the successive stages of SA, abstinence, and reexposure. This net increase in NAc firing at the time of nicotine-directed behavior occurs in association with an increase in animals' motivation to seek nicotine. The adaptations that occur in nicotine-exposed animals do not occur in animals exposed to sucrose. The NAc neurophysiological plasticity potentially contributes to compulsive tobacco use.


Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma.
Prostate carcinoma (CaP) is a leading cause of cancer-related death in men. We have previously determined the microRNA (miRNA) profile of primary CaP in comparison with nontumor prostate tissue. miRNAs are small, noncoding RNAs that inhibit protein synthesis on a posttranscriptional level by binding to the 3'-untranslated region (3'-UTR) of their target genes. In primary CaP tissue, we have previously found by miRNA sequencing that miR-375 and miR-200c were upregulated 9.1- and 4.5-fold, respectively. A computational analysis predicted the 3'-UTR of the SEC23A gene as a potential target for both miR-375 and miR-200c. Here, we show that the 3'-UTR of SEC23A mRNA is indeed a target for miR-375 and miR-200c and that both miRNAs downregulate Sec23A protein expression when ectopically expressed in human 293T cells. In primary samples of CaP, we found a direct correlation between reduction of SEC23A mRNA and overexpression of miR-375 but not of miR-200c. The reduced levels of Sec23A protein were inversely correlated to the increased amount of miR-375 in the LNCaP and DU145 CaP cell lines when compared with normal prostate fibroblasts. In primary CaP, we also detected decreased amounts of Sec23A protein when compared with corresponding normal prostate tissue. Ectopically overexpressed Sec23A in LNCaP and DU145 CaP cells significantly reduced the growth properties, indicating that Sec23A might play a role in the induction or growth of prostate carcinoma. Sec23A overexpression reduced cell growth but did not induce apoptosis, whereas inhibition of Sec23A stimulated cell proliferation.


Ability of physicians to diagnose influenza and usefulness of a rapid influenza antigen test in febrile returning travelers: A randomized controlled trial.
Fever is a frequent cause of medical consultation among returning travelers. The objectives of this study were to assess whether physicians were able to identify patients with influenza and whether the use of an influenza rapid diagnostic test (iRDT) modified the clinical management of such patients. Randomized controlled trial conducted at 2 different Swiss hospitals between December 2008 and November 2012. Inclusion criteria were 1) age ≥ 18 years, 2) documented fever of ≥ 38 °C or anamnestic fever + cough or sore throat within the last 4 days, 3) illness occurring within 14 days after returning from a trip abroad, 4) no definitive alternative diagnosis. Physicians were asked to estimate the likelihood of influenza on clinical grounds, and a single nasopharyngeal swab was taken. Thereafter patients were randomized into 2 groups: i) patients with iRDT (BD Directigen A + B) performed on the nasopharyngeal swab, ii) patients receiving usual care. A quantitative PCR to detect influenza was done on all nasopharyngeal swabs after the recruitment period. Clinical management was evaluated on the basis of cost of medical care, number of X-rays requested and prescription of anti-infective drugs. 100 eligible patients were referred to the investigators. 93 patients had a naso-pharyngeal swab for a PCR and 28 (30%) swabs were positive for influenza. The median probability of influenza estimated by the physician was 70% for the PCR positive cases and 30% for the PCR negative cases (p < 0.001). The sensitivity of the iRDT was only 20%, and specificity 100%. Mean medical cost for the patients managed with iRDT and without iRDT were USD 581 (95%CI 454-707) and USD 661 (95%CI 522-800) respectively. 14/60 (23%) of the patients managed with iRDT were prescribed antibiotics versus 13/33 (39%) in the control group (p = 0.15). No patient received antiviral treatment. Influenza was a frequent cause of fever among these febrile returning travelers. Based on their clinical assessment, physicians had a higher level of suspicion for influenza in PCR positive cases. The iRDT used in this study showed a disappointingly low sensitivity and can therefore not be recommended for the management of these patients. ClinicalTrials.gov NCT00821626.


Global Health and Emergency Care: Overcoming Clinical Research Barriers.
There are many barriers impeding the conduct of high-quality emergency care research, particularly in low- and middle-income countries. Several of these barriers were originally outlined in 2013 as part of the Academic Emergency Medicine Global Health and Emergency Care Consensus Conference. This paper seeks to establish a broader consensus on the barriers to emergency care research globally and proposes a comprehensive array of new recommendations to overcome these barriers. An electronic survey was conducted of a purposive sample of global emergency medicine research experts from around the world to describe the major challenges and solutions to conducting emergency care research in low-resource settings and rank them by importance. The Global Emergency Medicine Think Tank Clinical Research Working Group at the Society for Academic Emergency Medicine 2016 Annual Meeting utilized a modified Delphi technique for consensus-based decision making to categorize and expand upon these barriers and develop a comprehensive array of proposed solutions. The working group identified four broad categories of barriers to conducting emergency care research globally, including 1) the limited availability of research personnel, particularly those with prior research training; 2) logistic barriers and lack of standardization of data collection; 3) ethical barriers to conducting research in resource-limited settings, particularly when no local institutional review board is available; and 4) the relative dearth of funding for global emergency care research. Proposed solutions included building a diverse and interdisciplinary research team structured to promote mentorship of junior researchers, utilizing local research assistants or technologic tools such as telemedicine for language translation, making use of new tools such as mobile health (mHealth) to standardize and streamline data collection, identifying alternatives to local institutional review board approval and the use of community consent when appropriate, and increased advocacy for global emergency care research funding. Significant barriers to the conduct of high-quality global emergency care research persist, and innovative strategies need to be adopted to promote and grow the field of global emergency care research. This paper provides a global consensus on the most important barriers identified, as well as recommendations for cost-effective strategies for overcoming these barriers with the overall goal of promoting high-quality research and improving emergency care worldwide.


Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome.
Protein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.


The link between LGBTQ-supportive communities, progressive political climate, and suicidality among sexual minority adolescents in Canada.
Despite supportive structural changes to reduce stigma towards lesbian, gay, and bisexual, transgender, queer, and questioning (LGBTQ) Canadian residents, sexual minority youth still face disparities compared to heterosexual peers. We aimed to characterize LGBTQ-supportive environments and political climates, and examine their links to suicidal behavior among sexual minority adolescents in western Canada. Data were from the 2013 British Columbia Adolescent Health Survey, a cluster-stratified random cross-sectional survey of public school students in BC, Canada; We sampled 2678 self-identified LGB and mostly heterosexual students (69% girls) from 274 schools, representing an estimated provincial population of 24,624 sexual minority students in weighted models. Student reports of past-year suicidal ideation, suicidal attempts, and self-harm behaviors were merged with community-level data assessing diverse aspects of LGBTQ-supportive resources and progressive political climates in communities surrounding the schools. Adjusted multilevel models showed that for sexual minority adolescent girls, higher community LGBTQ-supportiveness predicted marginally significant lower suicidal ideation (aOR = 0.94, 95% CI [0.88, 1.01]) and suicidal attempts (aOR = 0.91, 95% CI [0.83, 1.00]) and significantly lower self-harm behaviors (aOR = 0.91, 95% CI [0.85, 0.98]). Further, progressive political climates predicted marginally significant lower suicidal ideation (aOR = 0.89, 95% CI [0.78, 1.02]) and significantly lower self-harm behaviors (aOR = 0.87, 95% CI [0.77, 0.99]). For sexual minority adolescent boys, no community-level variables were associated with suicidal behavior in adjusted models. Thus, LGBTQ-supportive communities and progressive political climates appear to be protective against suicidal behavior among sexual minority adolescent girls, but not sexual minority adolescent boys.


Latex vascular occlusion balloons: histopathologic evaluation in a high-flow aortocaval fistula model.
The treatment of carotid-cavernous fistulae with intravascular, detachable latex balloons has become an accepted method. However, the histologic changes associated with such balloon embolization in a high-flow fistula state have not been described. This study evaluated the microscopic findings in a series of 12 rats studied over a 3-month period using an aortocaval fistula model. Small latex balloons were introduced into the venae cavae of rats in whom aortocaval fistulae had been surgically created 3 weeks earlier. The histopathologic changes associated with treatment of these fistulae were examined at 1, 2, 4, 6, 8, and 12 weeks. These changes can be characterized by an acute phase with thrombus formation and acute inflammation, followed by intermediate (or subacute) and chronic phases with diminishing inflammation and progressively increasing fibrosis of the fistula site. The latex balloon became encased by the fibrotic reaction but remained nonadherent and was easily removed at every study interval. No abscess formation or persistent vasculitis was apparent, and foreign-body giant cell reaction was minimal. Closure of the high-flow fistula site required the balloon to remain inflated for at least 7-9 days.