[Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura].
In this study we report an individual of Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura. The initial symptom of this female patient was olfactory paranoia at age 17. Although that psychiatric symptom was well controlled under pharmacological treatment for two years, she developed olfactory paranoia as well as sialorrhea, dysarthria and finger tremor at age 20. A year later rigidity was also present in the extremities. At age 23, idiopathic thrombocytopenic purpura was found based on hematological examinations. Because her extrapyramidal symptoms were progressive, she was referred to our department to evaluate her neurologic condition. She was diagnosed as having Wilson's disease based on (1) the presence of Kayser-Fleischer rings, (2) extrapyramidal signs, and (3) a decreased level of serum copper and ceruloplasmin. T2 and FLAIR images of brain MRI showed hyperintense lesions in the putamen, thalamus and pontine tegmentum. Diffusion-weighted images also showed hyperintense lesions in the thalamus and pontine tegmentum. The biopsy specimen of the liver revealed chronic hepatitis with copper accumulation. Since D-penicillamine treatment was initiated, she has shown no olfactory paranoia and exacerbation of ITP. Her gait disturbance has also improved. Olfactory paranoia and ITP are rare clinical complications of Wilson's disease. Further analysis may warrant consideration of the pathophysiological mechanism of the psychiatric, hematological and neuroradiological condition seen in Wilson's disease.


Evaluation of Risk-Adjusted Home Time After Hospitalization for Heart Failure as a Potential Hospital Performance Metric.
Thirty-day home time, defined as time spent alive and out of a hospital or facility, is a novel, patient-centered performance metric that incorporates readmission and mortality. To characterize risk-adjusted 30-day home time in patients discharged with heart failure (HF) as a hospital-level quality metric and evaluate its association with the 30-day risk-standardized readmission rate (RSRR), 30-day risk-standardized mortality rate (RSMR), and 1-year RSMR. This hospital-level cohort study retrospectively analyzed 100% of Medicare claims data from 2 968 341 patients from 3134 facilities from January 1, 2012, to November 30, 2017. Home time, defined as time spent alive and out of a short-term hospital, skilled nursing facility, or intermediate/long-term facility 30 days after discharge. For each hospital, a risk-adjusted 30-day home time for HF was calculated similar to the Centers for Medicare & Medicaid Services risk-adjustment models for 30-day RSRR and RSMR. Hospitals were categorized into quartiles (lowest to highest risk-adjusted home time). The correlations between hospital rates of risk-adjusted 30-day home time and 30-day RSRR, 30-day RSMR, and 1-year RSMR were estimated using the Pearson correlation coefficient. Distribution of days lost from a perfect 30-day home time were calculated. Reclassification of hospital performance using 30-day home time vs 30-day RSRR was also evaluated. Overall, 2 968 341 patients (mean [SD] age, 81.0 [8.3] years; 53.6% female) from 3134 hospitals were included in this study. The median hospital risk-adjusted 30-day home time for patients with HF was 21.77 days (range, 8.22-28.41 days). Hospitals in the highest quartile of risk-adjusted 30-day home time (best-performing hospitals) were larger (mean [SD] number of beds, 285 [275]), with a higher volume of patients with HF (median, 797 patients; interquartile range, 395-1484) and were more likely academic hospitals (59.9%) with availability of cardiac surgery (51.1%) and cardiac rehabilitation (68.8%). A total of 72% of home time lost was attributable to stays in an intermediate- or long-term care facility (mean [SD], 2.65 [6.44] days) or skilled nursing facility (mean [SD], 3.96 [9.04] days), 13% was attributable to short-term readmissions (mean [SD], 1.25 [3.25] days), and 15% was attributable to death (mean [SD], 1.37 [6.04] days). Among 30-day outcomes, the 30-day RSRR and 30-day RSMR decreased in a graded fashion across increasing 30-day home time categories (correlation coefficients: 30-day RSRR and 30-day home time, -0.23, P < .001; 30-day RSMR and 30-day home time, -0.31, P < .001). Similar patterns of association were also noted for 1-year RSMR and 30-day home time (correlation coefficient, -0.35, P < .001). Thirty-day home time meaningfully reclassified hospital performance in 30% of the hospitals compared with 30-day RSRR and in 25% of hospitals compared with 30-day RSMR. In this study, 30-day home time among patients discharged after a hospitalization for HF was objectively assessed as a hospital-level quality metric using Medicare claims data and was associated with readmission and mortality outcomes and with reclassification of hospital performance compared with 30-day RSRR and 30-day RSMR.


Autoimmune Disease with Cardiac Valves Involvement: Libman-Sacks Endocarditis.
This case study aim to evaluate the response of steroid treatment for autoimmune endocarditis. Valvular heart disease is relatively rising in both congenital and acquired cases, but the autoimmune endocarditis remains rare. In this case, a 34 year old woman with clinical manifestation resembling systemic lupus erythematosus (SLE) is diagnosed with Libman-sacks Endocarditis. After six months of steroid treatment, her clinical manifestations and heart structure improved.


[Constrained competition in parallel drug importation: the case of simvastatin in Germany, the Netherlands, and the United Kingdom].
To examine the effects of parallel simvastatin importation on drug price in three of the main parallel importing countries in the European Union, namely the United Kingdom, Germany, and the Netherlands. To estimate the market share of parallel imported simvastatin and the unit price -both locally produced and parallel imported- adjusted by defined daily dose in the importing country and in the exporting country (Spain). Ordinary least squares regression was used to examine the potential price competition resulting from parallel drug trade between 1997 and 2002. The market share of parallel imported simvastatin progressively expanded (especially in the United Kingdom and Germany) in the period examined, although the price difference between parallel imported and locally sourced simvastatin was not significant. Prices tended to rise in the United Kingdom and Germany and declined in the Netherlands. We found no evidence of pro-competitive effects resulting from the expansion of parallel trade. The development of parallel drug importation in the European Union produced unexpected effects (limited competition) on prices that differ from those expected by the introduction of a new competitor. This is partially the result of drug price regulation scant incentives to competition and of the lack of transparency in the drug reimbursement system, especially due to the effect of informal discounts (not observable to researchers). The case of simvastatin reveals that savings to the health system from parallel trade are trivial. Finally, of the three countries examined, the only country that shows a moderate downward pattern in simvastatin prices is the Netherlands. This effect can be attributed to the existence of a system that claws back informal discounts.


PP2A-twins is antagonized by greatwall and collaborates with polo for cell cycle progression and centrosome attachment to nuclei in drosophila embryos.
Cell division and development are regulated by networks of kinases and phosphatases. In early Drosophila embryogenesis, 13 rapid nuclear divisions take place in a syncytium, requiring fine coordination between cell cycle regulators. The Polo kinase is a conserved, crucial regulator of M-phase. We have recently reported an antagonism between Polo and Greatwall (Gwl), another mitotic kinase, in Drosophila embryos. However, the nature of the pathways linking them remained elusive. We have conducted a comprehensive screen for additional genes functioning with polo and gwl. We uncovered a strong interdependence between Polo and Protein Phosphatase 2A (PP2A) with its B-type subunit Twins (Tws). Reducing the maternal contribution of Polo and PP2A-Tws together is embryonic lethal. We found that Polo and PP2A-Tws collaborate to ensure centrosome attachment to nuclei. While a reduction in Polo activity leads to centrosome detachments observable mostly around prophase, a reduction in PP2A-Tws activity leads to centrosome detachments at mitotic exit, and a reduction in both Polo and PP2A-Tws enhances the frequency of detachments at all stages. Moreover, we show that Gwl antagonizes PP2A-Tws function in both meiosis and mitosis. Our study highlights how proper coordination of mitotic entry and exit is required during embryonic cell cycles and defines important roles for Polo and the Gwl-PP2A-Tws pathway in this process.


Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus.
Accelerated atherosclerosis remains a major cause of death in late systemic lupus erythematosus (SLE). Omega-3 has been reported to have benefit for endothelial dysfunction, one of the earliest stages of atherosclerosis, and to reduce disease activity in SLE. We performed a randomized, double-blind placebo-controlled trial to examine the effect of Omega-3 on endothelial function, disease activity, inflammatory markers and lipids in SLE. SLE patients (n = 85, mean age 47, 55% Caucasian, 38% African-American, 94% female) were randomly assigned to 3 g of Omega-3 (Lovaza, GSK) versus placebo for 12 weeks. Endothelial function was measured at baseline and at 12 weeks using flow-mediated dilation, calculated using high-resolution B-mode ultrasound of the brachial artery diameter in response to vasoactive stimuli (hyperemia). Disease activity was measured using the physician global assessment and SELENA-SLEDAI score. Inflammatory markers (sICAM-1, sVCAM-1, IL-6) and fasting lipid profile were done at baseline and 12-week follow-up. There was no difference between the treatment groups with respect to changes in flow-mediated dilation parameters or disease activity. An average increase in LDL cholesterol of 3.11 mg/dL (±21.99) was found with Omega-3 versus a decrease of 1.87 mg/dL (±18.29) with placebo (p = 0.0266). In this trial, Omega-3 did not improve endothelial function, disease activity, nor reduce inflammatory markers in SLE. Longer trials might be required if there are delayed clinical effects. There was evidence that Omega-3 may increase LDL cholesterol, but not the LDL/HDL ratio.


Validity of a condition specific outcome measure for fragile X syndrome: the Aberrant Behaviour Checklist-utility index.
The purpose of this study was to assess the construct validity of the Aberrant Behaviour Checklist-utility index (ABC-UI) by examining the relationship between healthcare resource utilisation by patients with fragile X syndrome (FXS) as well as burden experienced by their caregivers. In 2011, a total of 350 US caregivers of individuals with FXS completed a questionnaire that captured information on FXS-related burden as well as the ABC-Community. Using the ABC-UI, a condition-specific outcome measure derived from the ABC-Community, five utility index categories were created: very low (0.00-0.33); low (0.34-0.66); moderate (0.67-0.77); high (0.78-0.89); and very high (0.90-1.00). Multivariable regression models examined the association between the utility value and nine burden-related outcomes. Approximately 2% of individuals with FXS were in the very low utility index category, 31% low, 27% moderate, 38% high and 3% very high. The median utility value was 0.74. Women with FXS and adults 18 years and older had higher values. Regression results indicate that individuals with higher utility values were more likely to have fewer specialist visits, use fewer prescription medications, need fewer hours of unpaid caregiving, inflict fewer caregiver injuries and have caregivers with fewer mental health provider visits. The ABC-UI appears to function well as condition-specific outcome measure, and as an indicator of health-related quality-of-life and economic burden in individuals with FXS. Among patients with FXS in the US and their caregivers, significant differences in health care resource utilisation and burden exist across health state utility categories.


Role of enzymatic activity in muscle damage and cytotoxicity induced by Bothrops asper Asp49 phospholipase A2 myotoxins: are there additional effector mechanisms involved?
Viperid venoms often contain mixtures of Asp49 and Lys49 PLA2 myotoxin isoforms, relevant to development of myonecrosis. Given their difference in catalytic activity, mechanistic studies on each type require highly purified samples. Studies on Asp49 PLA2s have shown that enzyme inactivation using p-bromophenacyl bromide (p-BPB) drastically affects toxicity. However, based on the variable levels of residual toxicity observed in some studies, it has been suggested that effector mechanisms independent of catalysis may additionally be involved in the toxicity of these enzymes, possibly resembling those of the enzymatically inactive Lys49 myotoxins. A possibility that Lys49 isoforms could be present in Asp49 PLA2 preparations exists and, if undetected in previous studies, could explain the variable residual toxicity. This question is here addressed by using an enzyme preparation ascertained to be free of Lys49 myotoxins. In agreement with previous reports, inactivation of the catalytic activity of an Asp49 myotoxin preparation led to major inhibition of toxic effects in vitro and in vivo. The very low residual levels of myotoxicity (7%) and cytotoxicity (4%) observed can be attributed to the low, although detectable, enzyme remaining active after p-BPB treatment (2.7%), and would be difficult to reconcile with the proposed existence of additional catalytic-independent toxic mechanisms. These findings favor the concept that the effector mechanism of toxicity of Asp49 PLA2 myotoxins from viperids fundamentally relies on their ability to hydrolyze phospholipids, arguing against the proposal that membrane disruption may also be caused by additional mechanisms that are independent of catalysis.


Using economic instruments to develop effective management of invasive species: insights from a bioeconomic model.
Economic growth is recognized as an important factor associated with species invasions. Consequently, there is increasing need to develop solutions that combine economics and ecology to inform invasive species management. We developed a model combining economic, ecological, and sociological factors to assess the degree to which economic policies can be used to control invasive plants. Because invasive plants often spread across numerous properties, we explored whether property owners should manage invaders cooperatively as a group by incorporating the negative effects of invader spread in management decisions (collective management) or independently, whereby the negative effects of invasive plant spread are ignored (independent management). Our modeling approach used a dynamic optimization framework, and we applied the model to invader spread using Linaria vulgaris. Model simulations allowed us to determine the optimal management strategy based on net benefits for a range of invader densities. We found that optimal management strategies varied as a function of initial plant densities. At low densities, net benefits were high for both collective and independent management to eradicate the invader, suggesting the importance of early detection and eradication. At moderate densities, collective management led to faster and more frequent invader eradication compared to independent management. When we used a financial penalty to ensure that independent properties were managed collectively, we found that the penalty would be most feasible when levied on a property's perimeter boundary to control spread among properties. At the highest densities, the optimal management strategy was "do nothing" because the economic costs of removal were too high relative to the benefits of removal. Spatial variation in L. vulgaris densities resulted in different optimal management strategies for neighboring properties, making a formal economic policy to encourage invasive species removal critical. To accomplish the management and enforcement of these economic policies, we discuss modification of existing agencies and infrastructure. Finally, a sensitivity analysis revealed that lowering the economic cost of invader removal would strongly increase the probability of invader eradication. Taken together, our results provide quantitative insight into management decisions and economic policy instruments that can encourage invasive species removal across a social landscape.


Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice.
Sevoflurane, the most commonly used inhaled anesthetic in pediatric anesthesia, has been reported to induce cognitive impairment in developing brain in preclinical and clinical settings. However, the mechanism and therapeutic measures of this developmental neurotoxicity need to be further investigated. Resveratrol, a natural polyphenolic agent, has been reported to improve cognitive function in neurological disorders and aging models through anti-inflammatory activity. However, its effect on sevoflurane-induced cognitive impairment in developing mice remains unknown. The present study was designed to investigate the therapeutic potential of resveratrol on sevoflurane-induced cognitive impairment. Six-day-old mice received anesthesia with 3% sevoflurane 2 h daily on postnatal days (P) 6, P7 and P8. About 100 mg/kg resveratrol were intraperitoneally administered for 6 consecutive days to neonatal mice before anesthesia. Sevoflurane exposure significantly suppressed the expression of Sirtuin 1 (SIRT1) and activated microglia in hippocampi. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were markedly increased after sevoflurane exposure. Strikingly, resveratrol pretreatment ameliorated sevoflurane-induced SIRT1 inhibition and microglial activation. Of note, resveratrol reversed sevoflurane-induced imbalance of M1/M2 microglia ratio revealed by increasing mRNA level of clusters of differentiation 206 (CD206) and decreasing mRNA levels of clusters of differentiation 86 (CD86) and suppressor of cytokine signaling 3 (SOCS3). Consequently, sevoflurane-induced cognitive impairment in developing mice was ameliorated by resveratrol pretreatment. Taken together, repeated sevoflurane exposure to the developing brain resulted in SIRT1 inhibition, NF-κB acetylation, and microglial activation. Resveratrol pretreatment ameliorated cognitive impairment in developing mice received sevoflurane exposure by modulating SIRT1-NF-κB pathway in microglia. In this regard, our findings open novel directions to explore promising therapeutic targets for preventing the developmental neurotoxicity of sevoflurane.


Redox redux: protecting the ischemic myocardium.
Cardiac ischemia-reperfusion (I-R) injury occurs upon prompt restoration of blood flow to the ischemic myocardium after an acute myocardial infarction. Interestingly, many of the features of I-R injury are related to impaired mitochondrial signaling and mitochondrial dysfunction. Restoring cardiac energy bioavailability and reduction-oxidation (redox) signaling are therefore important in recovery after I-R injury. In this issue of the JCI, Yoshioka and colleagues describe an important and unexpected role for thioredoxin-interacting protein (TXNIP) in the control of mitochondrial respiration and cell energy metabolism. Their findings could open the door for development of TXNIP-targeted therapeutic approaches for the treatment of cardiac I-R injury.


Superantigen-mediated deletion of specific T cell receptor V beta subsets in the SCID-hu Thy/Liv mouse is induced by staphylococcal enterotoxin B, but not HIV-1.
Infection by HIV-1 has been associated with perturbations in the TCR V beta repertoire, suggesting the involvement of a superantigen. Among the hallmarks of superantigens is the capacity to delete T cells bearing specific TCR V beta families in the developing thymus. To verify the presence of a superantigen in HIV-1, we analyzed the SCID-hu Thy/Liv TCR V beta repertoire within CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocytes subsets by flow cytometry using a panel of Abs recognizing about 60% of the TCR repertoire following injection of SEB or infection by two different HIV-1 isolates. Seven days following SEB injection, thymocyte subsets bearing TCR V beta 3, V beta 12, V beta 17, and V beta 20, but not V beta 5 or V beta 8 , were deleted relative to mock-injected mice. In contrast, no changes were observed in the TCR V beta repertoire in CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocyte subsets after infection with HIV-1. The T cell depletion caused by HIV-1 infection is most likely not mediated by an HIV-encoded superantigen.


Barriers to Participation in a Community-Based Program to Control Transmission of Taenia solium in Peru.
Infection of the brain with Taenia solium larvae (neurocysticercosis) is a leading cause of preventable epilepsy worldwide. Effective and sustainable strategies to control parasite transmission in rural endemic communities are needed to prevent the disease. Surveillance and targeted intervention around infected pigs (ring control strategy) have been shown to be effective when carried out by research teams. However, this strategy has not been implemented or tested as a community-based program. In this small trial in northern Peru, eight villages were randomly assigned to community-led surveillance and treatment (five villages, 997 residents) or control (three villages, 1,192 residents). In intervention villages, community-led surveillance and reporting were promoted by community health workers, radio advertisement, and school and household education. Each suspected pig infection was verified, with confirmed cases resulting in treatment with niclosamide for taeniasis and oxfendazole for pigs in clusters of homes nearby. No incentives beyond human and pig treatment were offered. Control villages received basic disease education but no treatment intervention in response to reports. Despite 14 case reports, community-based replication of ring control strategy did not replicate prior results. After 12 months, there was no change in seroincidence in intervention villages between the baseline and study end, and no difference compared with control villages. There was no difference in prevalence of taeniasis or porcine cysticercosis at study end. Community members described lack of knowledge as the main reason for not reporting infected pigs. Further exploration of methods to transfer ring strategy and other control interventions for cysticercosis to the community is needed.


Effects of communicating uncertainty descriptions in hazard identification, risk characterization, and risk protection.
Uncertainty is a crucial issue for any risk assessment. Consequently, it also poses crucial challenges for risk communications. Many guidebooks advise reporting uncertainties in risk assessments, expecting that the audience will appreciate this disclosure. However, the empirical evidence about the effects of uncertainty reporting is sparse and inconclusive. Therefore, based on examples of potential health risks of electromagnetic fields (EMF), three experiments were conducted analysing the effects of communicating uncertainties separately for hazard identification, risk characterisation and risk protection. The setups aimed to explore how reporting and how explaining of uncertainty affects dependent variables such as risk perception, perceived competence of the risk assessors, and trust in risk management. Each of the three experiments used a 2x2 design with a first factor presenting uncertainty descriptions (as used in public controversies on EMF related health effects) or describing a certainty conditions; and a second factor explaining the causes of uncertainties (by pointing at knowledge gaps) or not explaining them. The study results indicate that qualitative uncertainty descriptions regarding hazard identification reduce the confidence in the professional competencies of the assessors. In contrast, a quantitative uncertainty description in risk characterisation-regarding the magnitude of the risk-does not affect any of the dependent variables. Concerning risk protection, trust in exposure limit values is not affected by qualitative uncertainty information. However, the qualitative description of uncertainty regarding the adequacy of protection amplifies fears. Furthermore, explaining this uncertainty results in lower text understandability.


Tracking invasion histories in the sea: facing complex scenarios using multilocus data.
In recent years, new analytical tools have allowed researchers to extract historical information contained in molecular data, which has fundamentally transformed our understanding of processes ruling biological invasions. However, the use of these new analytical tools has been largely restricted to studies of terrestrial organisms despite the growing recognition that the sea contains ecosystems that are amongst the most heavily affected by biological invasions, and that marine invasion histories are often remarkably complex. Here, we studied the routes of invasion and colonisation histories of an invasive marine invertebrate Microcosmus squamiger (Ascidiacea) using microsatellite loci, mitochondrial DNA sequence data and 11 worldwide populations. Discriminant analysis of principal components, clustering methods and approximate bayesian computation (ABC) methods showed that the most likely source of the introduced populations was a single admixture event that involved populations from two genetically differentiated ancestral regions--the western and eastern coasts of Australia. The ABC analyses revealed that colonisation of the introduced range of M. squamiger consisted of a series of non-independent introductions along the coastlines of Africa, North America and Europe. Furthermore, we inferred that the sequence of colonisation across continents was in line with historical taxonomic records--first the Mediterranean Sea and South Africa from an unsampled ancestral population, followed by sequential introductions in California and, more recently, the NE Atlantic Ocean. We revealed the most likely invasion history for world populations of M. squamiger, which is broadly characterized by the presence of multiple ancestral sources and non-independent introductions within the introduced range. The results presented here illustrate the complexity of marine invasion routes and identify a cause-effect relationship between human-mediated transport and the success of widespread marine non-indigenous species, which benefit from stepping-stone invasions and admixture processes involving different sources for the spread and expansion of their range.


[11 beta-hydroxysteroid dehydrogenase type 2 activity in Chilean patients with hypertension].
Half of hypertensive patients with low plasma renin activity have a primary hyperaldosteronism. Among the remaining half, 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) deficiency plays an important role. This enzyme catalyzes the conversion of cortisol to cortisone, avoiding the interaction of cortisol with the mineralocorticoid receptor. If the enzyme fails, cortisol will stimulate sodium and water reabsorption and increase blood pressure. To determine biochemical alterations, suggestive of 11 beta HSD2 deficiency, in low-renin hypertensive patients. Twenty eight hypertensive patients with a plasma renin activity of less than 0.5 ng/ml/h and with a plasma aldosterone of less than 5 ng/dl were studied. Twenty eight normotensive patients were studied as controls. Serum cortisol (RIA), cortisone (ELISA) and the serum cortisol/cortisone ratio were determined in all of them, between 9 and 10 AM. Measurements were confirmed by high pressure liquid chromatography. The serum cortisol/cortisone ratio was considered abnormal when its Ln (cortisol/cortisone) value was over 2 standard deviations of the mean. Serum cortisol was higher in hypertensive subjects than in controls (11.1 +/- 3.3 and 9.2 +/- 2.8 micrograms/dl, respectively; p < 0.05). No differences were observed in serum cortisone (3.4 +/- 1.3 and 3.7 +/- 1.2 micrograms/dl, respectively). Four hypertensive subjects had an abnormally high Ln (cortisol/cortisone) value (1.86; 1.73; 2.07 and 2.01, considering a normal value of less than 1.61). Four of 28 hypertensive subjects with low plasma renin activity and aldosterone had biochemical alterations suggestive of 11 beta HSD2 deficiency.


Fluorescence - modern method of the diagnosis of chronic wounds on the example of venous leg ulcer.
Fluorescence imaging has become a method for bacterial visualisation in chronic wounds for the last few years. MolecuLight i:X (MolecuLight, Inc, ON, Canada) is a handheld device, which enables quick diagnostics to determine both the type and location of pathogens present in the wound and on the skin. By means of fluorescent light illumination the tissues populated by pathogenic bacteria emit red or cyan fluorescent signatures, depending on the type of the pathogen: red fluorescence signal is emitted by Staphylococcus and Escherichia coli among others, while Pseudomonas aeruginosa produce cyan fluorescence. The fluorescence image also presents the spatial pattern of bacterial load, which creates bacterial mapping of the wound and may be used by a clinician for targeted sampling or debridement, among others. This study presents the method of microbiological fluorescent imaging and two case studies of patients with venous leg ulcers. In both cases, the sample for microbiological testing was obtained by means of a swab stick. The results obtained from fluorescent imaging showed moderate-to-heavy bacterial load, which corresponded with the results from microbiology laboratory. Thanks to quick diagnostics with the use of MolecuLight i:X device, instant implementation of targeted topical actions such as wound hygiene, skin disinfection, appropriate dressing choice and curative treatment among others was possible. Our observations are consistent with the reports from other facilities.


Clinical Characteristics of Patients with Schizophrenia Maintained without Antipsychotics: A Cross-sectional Survey of a Case Series.
While antipsychotics are necessary for relapse prevention in the treatment of schizophrenia in general, some minority of patients may be maintained without continuous antipsychotic treatment. However, the characteristics of such patients are not well known and previous reports have not evaluated key elements such as physical comorbidities and functioning. Among 635 patients with schizophrenia who participated in a 12-year follow-up, those who were maintained without antipsychotic treatment for at least one year after the study were investigated. The patients underwent comprehensive assessments, including Positive and Negative Syndrome Scale (PANSS) for psychopathology, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) for physical comorbidities, and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz), Barthel Index, and EuroQoL five dimensions (EQ5D) for function. Six patients were included (mean ± standard deviation age, 66.8 ± 17.4 years; 4 inpatients). The four inpatients were old (77.8 ± 4.8 years) and chronically ill (duration of illness, 49.3 ± 12.5 years) with a high PANSS score (total score, 118.0 ± 9.8; negative syndrome subscale, 41.3 ± 6.9), low functioning (FACT-Sz, 9.8 ± 3.6; Barthel Index, 8.8 ± 9.6), and serious physical comorbidities (CIRS-G, 15.5 ± 1.1). By contrast, the two outpatients were relatively young (45.0 ± 12.0 years) and clinically in good condition (PANSS total score, 44.5 ± 0.5; Barthel Index, 100 for both; EQ5D, 0.85 ± 0.04). Although the number is limited, two types of patients with schizophrenia were identified who were free from ongoing antipsychotic treatment; 1) older chronic inpatients with serious physical comorbidities, and 2) younger outpatients with milder impairments. Future explorations are needed to identify those who will be successfully withdrawn from continuous antipsychotic treatment.


Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen.
The Ku complex, a heterodimer of 86- and 70-kD proteins, is a nuclear DNA-binding autoantigen. However, hydrophobicity analysis of the deduced amino acid sequence of the 70-kD protein had strongly suggested that this might also be a membrane protein. In the present study, using antibodies to synthetic peptides and a polyclonal antiserum to the purified protein, we show that the 70-kD protein of the Ku complex is present in isolated plasma membranes of human cells. By indirect immunofluorescence microscopy and fluorescein-activated cell sorting, we demonstrate that this autoantigen is exposed on the cell surface. In addition, we have identified several domains of the protein that are exposed. Our study provides one of the first demonstrations of a eukaryotic, nuclear DNA-binding protein that is also on the cell membrane. Moreover, our results might help explain how autoantibodies to the Ku autoantigen could target cells for an autoimmune attack.


Sexual dysfunction, HIV, and AIDS in men who have sex with men.
HIV infection is associated with sexual dysfunction. Using validated instruments, we investigated the relationship between HIV/AIDS and sexual function in a contemporary cohort of men who have sex with men (MSM). An anonymous Internet-based survey was disseminated to MSM via organizations and social networking sites that cater to this population. Information on ethnodemographic variables, health status (including HIV status, disease stage, and other health conditions), and sexual behavior was collected. Men were categorized as HIV-negative, HIV-positive/AIDS-negative, or HIV-positive /AIDS-positive. A modified validated version of the International Index of Erectile Function (IIEF) for use in MSM and the Premature Ejaculation Diagnostic Tool (PEDT) were used to stratify risk of sexual dysfunction. The study cohort included 1361 men (236 of whom were HIV-positive) who provided complete data on HIV status, IIEF, and PEDT. There was a significant trend toward greater prevalence of erectile dysfunction (ED) in men with progressive HIV infection 40-59 years of age relative to age matched HIV-negative men (p=0.02). In a logistic regression model controlling for other variables, HIV infection without AIDS was not associated with greater odds of ED; however, HIV infection with AIDS was associated with greater odds of ED (p=0.006). In a separate logistic regression model, HIV infection with or without AIDS was not significantly associated with greater odds of premature ejaculation (p>0.05). Use of phosphodiesterase 5 (PDE5) inhibitor drugs was much more common in HIV-infected men. HIV infection is a risk factor for poorer sexual function primarily due to higher risk of erectile dysfunction in men with AIDS.


Microtubule organization in three-dimensional confined geometries: evaluating the role of elasticity through a combined in vitro and modeling approach.
Microtubules or microtubule bundles in cells often grow longer than the size of the cell, which causes their shape and organization to adapt to constraints imposed by the cell geometry. We test the reciprocal role of elasticity and confinement in the organization of growing microtubules in a confining box-like geometry, in the absence of other (active) microtubule organizing processes. This is inspired, for example, by the cortical microtubule array of elongating plant cells, where microtubules are typically organized in an aligned array transverse to the cell elongation axis. The method we adopt is a combination of analytical calculations, in which the polymers are modeled as inextensible filaments with bending elasticity confined to a two-dimensional surface that defines the limits of a three-dimensional space, and in vitro experiments, in which microtubules are polymerized from nucleation seeds in microfabricated chambers. We show that these features are sufficient to organize the polymers in aligned, coiling configurations as for example observed in plant cells. Though elasticity can account for the regularity of these arrays, it cannot account for a transverse orientation of microtubules to the cell's long axis. We therefore conclude that an additional active, force-generating process is necessary to create a coiling configuration perpendicular to the long axis of the cell.


Whole blood Fe isotopic signature in a sub-Saharan African population.
The Fe isotopic composition of an individual's whole blood has recently been shown to be an interesting clinical indicator of Fe status. The present study aimed to evaluate the influence of several endemic characteristics of a representative population of the South Kivu province, an Fe-rich volcanic African region, on the whole blood Fe isotopic composition. Both diabetes mellitus and the ferroportin Q248H mutation are very common in Africa and are strongly associated with impairments in Fe metabolism. Fe isotopic analysis of whole blood samples was carried out using multi-collector inductively coupled plasma-mass spectrometry (after chromatographic isolation of the target element). Forty-two male subjects (between 48 and 59 years old) living in Bukavu (South Kivu) were enrolled in this study. Among the selected population, wild-type subjects and subjects presenting the ferroportin Q248H mutation (heterozygotes and homozygotes) were included. Within each group, diabetic and non-diabetic patients were considered. The whole blood δ56Fe value ranged from -3.09‰ to -2.41‰. The δ56Fe value shows a significant negative correlation with the ferritin concentration. No correlation could be established between the whole blood δ56Fe value and the transferrin concentration, transferrin saturation or serum Fe concentration. The ferroportin Q248H mutation did not seem to have affected the whole blood Fe isotopic signature. The whole blood δ56Fe values were significantly higher in diabetic subjects than in non-diabetic subjects and showed a significant negative correlation with body mass index (BMI) values.


Symptoms and risk factors of Cryptosporidium hominis infection in children: data from a large waterborne outbreak in Sweden.
Cryptosporidium is a major cause of diarrheal disease worldwide. In developing countries, this infection is endemic and in children, associated with growth faltering and cognitive function deficits, with the most severe impact on those aged <2 years. Little has been reported about symptoms and risk factors for children in industrialized countries, although the disease incidence is increasing in such regions. In November 2010, a large waterborne outbreak of C. hominis occurred in the city of Östersund in Sweden. Approximately 27,000 of the 60,000 inhabitants were symptomatic. We aimed to describe duration of symptoms and the risk factors for infection with C. hominis in children aged <15 years in a Western setting. Within 2 months after a boil water advisory, a questionnaire was sent to randomly selected inhabitants of all ages, including 753 children aged <15 years. Those with ≥3 loose stools/day were defined as cases of diarrhoea. The response rate was 70.3%, and 211 children (39.9%) fulfilled the case definition. Mean duration of diarrhoea was 7.5 days (median 6, range 1-80 days). Recurrence, defined as a new episode of diarrhoea after ≥2 days of normal stools, occurred in 52.5% of the cases. Significant risk factors for infection, besides living within the distribution area of the contaminated water plant, included a high level of water consumption, male sex, and a previous history of loose stools. The outbreak was characterized by high attack and recurrence rates, emphasizing the necessity of water surveillance to prevent future outbreaks.


The Drosophila disembodied gene controls late embryonic morphogenesis and codes for a cytochrome P450 enzyme that regulates embryonic ecdysone levels.
Ecdysteroids regulate a wide variety of cellular processes during arthropod development, yet little is known about the genes involved in the biosynthesis of these hormones. Previous studies have suggested that production of 20-hydroxyecdysone in Drosophila and other arthropods involves a series of cytochrome P450 catalyzed hydroxylations of cholesterol. In this report, we show that the disembodied (dib) locus of Drosophila codes for a P450-like sequence. In addition, we find that dib mutant embryos have very low titers of ecdysone and 20-hydroxyecdysone (20E) and fail to express IMP-E1 and L1, two 20E-inducible genes, in certain tissues of the embryo. In situ hybridization studies reveal that dib is expressed in a complex pattern in the early embryo, which eventually gives way to restricted expression in the prothoracic portion of the ring gland. In larval and adult tissues, dib expression is observed in the prothoracic gland and follicle cells of the ovaries respectively, two tissues known to synthesize ecdysteroids. Phenotypic analysis reveals that dib mutant embryos produce little or no cuticle and exhibit severe defects in many late morphogenetic processes such as head involution, dorsal closure and gut development. In addition, we examined the phenotypes of several other mutants that produce defective embryonic cuticles. Like dib, mutations in the spook (spo) locus result in low embryonic ecdysteroid titers, severe late embryonic morphological defects, and a failure to induce IMP-E1. From these data, we conclude that dib and spo likely code for essential components in the ecdysone biosynthetic pathway and that ecdysteroids regulate many late embryonic morphogenetic processes such as cell movement and cuticle deposition.


Microbial diversity of Emalahleni mine water in South Africa and tolerance ability of the predominant organism to vanadium and nickel.
The present study aims firstly at determining the microbial diversity of mine-water collected in Emalahleni, South Africa and secondly isolating and characterizing the most dominant bacterial species found in the mine water in terms of its resistance to both V(5+) and Ni(2+) in a modified wastewater liquid media. The results revealed a microbial diversity of 17 orders, 27 families and 33 genera were found in the mine-water samples with Marinobacteria (47.02%) and Anabaena (17.66%) being the most abundant genera. Considering their abundance in the mine-water samples, a species of the Marinobacter genera was isolated, identified, and characterised for metal tolerance and removal ability. The MWI-1 isolate (Marinobacter sp. MWI-1 [AB793286]) was found to be closely related to Marinobacter goseongensis at 97% of similarity. The isolate was exposed to various concentrations of Ni(2+) and V(5+) in wastewater liquid media and its tolerance to metals was also assessed. The MWI-1 isolate could tolerate V(5+) and Ni(2+) separately at concentrations (in terms of MIC) up to 13.41 ± 0.56 mM and 5.39 ± 0.5 mM at pH 7, whereas at pH 3, the tolerance limit decrease to 11.45 ± 0.57 mM and 2.67 ± 0.1 mM, respectively. The removal of V(5+) and Ni(2+) in liquid media was noted to gradually decrease with a gradual increase of the test metals. A significant difference (p<0.05) between V(5+) and Ni(2+) removal was noted. Marinobacter sp. MWI-1 achieved the maximum permissible limit of 0.1 mg-V(5+)/L prescribed by UN-FAO at 100 mg/L, while at 200 mg/L only V(5+) was removed at approximately 95% and Ni(2+) at 47%. This study suggests that mine-water indigenous microorganisms are the best solution for the remediation of polluted mine water.


Effects of a variety of food extracts and juices on the specific binding ability of norovirus GII.4 P particles.
The effects of 13 food extracts and juices, including shellfish, fruits, and vegetables, on the binding ability of human norovirus (NoV) were examined, using P particles of human NoV GII.4 as a research surrogate. The enhancements (positive values) or reductions (negative values) of NoV P particle detection (changes in optical density at 450 nm) in the presence of different food extracts and juices as compared with P particles diluted in phosphate-buffered saline were tested by saliva-binding, enzyme-linked immunosorbent assay in triplicate. In the presence of different food extracts and juices at different concentrations, an increase or decrease of the receptor-binding ability of the NoV P particles was observed. Due to a higher specific binding and thus a higher accumulation of the viral particles, oysters may be contaminated with human NoV more often than other shellfish species (mussel, hard clams, and razor clams). Cranberry and pomegranate juices were shown to reduce the specific binding ability of human NoV P particles. No such binding inhibition effects were observed for the other tested extracts of fresh produce (strawberry, blackberry, blueberry, cherry tomato, spinach, romaine lettuce) or, notably, for raspberry, which has been associated with human NoV outbreaks.


[Trends in pediatric bacterial meningitis in Japan (2003-2004)].
We surveyed the epidemiology of pediatric bacterial meningitis between January 2003 and December 2004 in Japan, with the following results: Bacterial meningitis cases numbered 233 (132 boys, 98 girls, and 3 unidentified), equivalent to 1.13-1.6 children of 1000 hospitalized in pediatrics per year. The age distribution for the infections was the highest under 1 year of age, decreasing with increasing age. Haemophilus influenzae was the most common pathogen, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. The relationship between causactive pathogens and age distribution was as follows: group B. streptococcus and E. coli were major pathogens below 4 months of age and H. influenzae and S. pneumoniae were major pathogens above 4 months of age. Susceptibility tests at each facility demonstrated that 65.0% of H. influenzae isolates and 83.0% of S. pneumoniae isolates in 2004 were drug-resistant. Ampicillin and cephem antibiotics are currently effective against GBS, E. coli and Listeria so a combination of ampicillin and cephem antibiotics is used first line at many facilities for patients below 4 months of age. A combination of carbapenem which showed effective against PRSP and cephem which showed effective against H. influenzae is the first choice in childhood bacterial meningitis for patients above 4 months of age.


Assessing global risk factors for non-fatal injuries from road traffic accidents and falls in adults aged 35-70 years in 17 countries: a cross-sectional analysis of the Prospective Urban Rural Epidemiological (PURE) study.
To assess risk factors associated with non-fatal injuries (NFIs) from road traffic accidents (RTAs) or falls. Our study included 151 609 participants from the Prospective Urban Rural Epidemiological study. Participants reported whether they experienced injuries within the past 12 months that limited normal activities. Additional questions elicited data on risk factors. We employed multivariable logistic regression to analyse data. Overall, 5979 participants (3.9% of 151 609) reported at least one NFI. Total number of NFIs was 6300: 1428 were caused by RTAs (22.7%), 1948 by falls (30.9%) and 2924 by other causes (46.4%). Married/common law status was associated with fewer falls, but not with RTA. Age 65-70 years was associated with fewer RTAs, but more falls; age 55-64 years was associated with more falls. Male versus female was associated with more RTAs and fewer falls. In lower-middle-income countries, rural residence was associated with more RTAs and falls; in low-income countries, rural residence was associated with fewer RTAs. Previous alcohol use was associated with more RTAs and falls; current alcohol use was associated with more falls. Education was not associated with either NFI type. This study of persons aged 35-70 years found that some risk factors for NFI differ according to whether the injury is related to RTA or falls. Policymakers may use these differences to guide the design of prevention policies for RTA-related or fall-related NFI.


Dietary inflammatory potential is associated with higher odds of hepatic steatosis in US adults: a cross-sectional study.
Inflammation plays a critical role in the progression of chronic liver diseases, and diet can modulate inflammation. Whether an inflammatory dietary pattern is associated with higher risk of hepatic steatosis or fibrosis remains unclear. We aimed to investigate the associations between inflammatory dietary pattern and the odds of hepatic steatosis and fibrosis. In this nationwide cross-sectional study, diet was measured using two 24-h dietary recalls. Empirical dietary inflammatory pattern (EDIP) score was derived to assess the inflammatory potential of usual diet, which has been validated to highly predict inflammation markers in the study population. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were derived from FibroScan to define steatosis and fibrosis, respectively. US National Health and Nutrition Examination Survey. 4171 participants aged ≥18 years. A total of 1436 participants were diagnosed with S1 steatosis (CAP ≥ 274 dB/m), 255 with advanced fibrosis (LSM ≥ 9·7 kPa). Compared with those in the lowest tertile of EDIP-adherence scores, participants in the highest tertile had 74 % higher odds of steatosis (OR: 1·74, 95 % CI (1·26, 2·41)). Such positive association persisted among never drinkers, or participants who were free of hepatitis B and/or C. Similarly, EDIP was positively associated with CAP in multivariate linear model (P < 0·001). We found a non-significant association of EDIP score with advanced fibrosis or LSM (P = 0·837). Our findings suggest that a diet score that is associated with inflammatory markers is associated with hepatic steatosis. Reducing or avoiding pro-inflammatory diets intake might be an attractive strategy for fatty liver disease prevention.


The research design and methodological issues for the Cash and Counseling Evaluation.
To provide an overview of the design, research questions, data sources, and methods used to evaluate the Cash and Counseling Demonstration and resolution of analytic concerns that arose. The methodology was designed to provide statistically rigorous estimates while presenting the findings in a manner easily accessible to a broad, non-technical audience. Eligible Medicaid beneficiaries in Arkansas, Florida, and New Jersey who volunteered to participate in the demonstration were randomly assigned to receive an allowance and direct their own Medicaid supportive services as Cash and Counseling consumers (the treatment group) or to rely on Medicaid services as usual (the control group). The demonstration included elderly and non-elderly adults in all three states and children in Florida. Both age groups in Arkansas and New Jersey and the elderly adults group in Florida primarily included individuals with physical disabilities. In Florida, the children and non-elderly adults primarily included individuals with developmental disabilities. The intervention was conducted from 1999 through 2003. Data included baseline and 9-month follow-up surveys of consumers, surveys of the primary informal caregiver and the primary paid worker for sample members, program data, interviews with program staff, and Medicaid and Medicare claims data. Descriptive data analyses were conducted on program participation, program implementation, and the experiences of hired workers. Program impacts on consumers, caregivers, and costs were estimated using an intent-to-treat-approach, comparing the regression-adjusted means of outcomes for the full treatment and control groups. A broad set of control variables from the baseline interview and prior Medicaid claims data controlled for possible preexisting differences. Ordinal scale responses were converted to binary outcome indicators for high and for low values for ease of presentation and interpretation of effects. Two-tailed statistical tests of the estimated effects were conducted at the .05 level. Separate estimates were provided for each state and for each age group. Sensitivity tests were conducted of the robustness of estimates to outliers (for continuous outcome measures) and to proxy use. PRINCIPAL FINDINGS/CONCLUSION: The experimental design, high survey response rates, and available sample sizes led to valid, unbiased estimates of program impacts, with adequate power to detect moderate-size impacts on most outcomes for the key age subgroups examined. For certain survey-based outcome measures related to satisfaction with paid care, the sample had to be restricted to those who received care and those without proxy respondents who were also hired workers. Sensitivity tests suggest that these necessary restrictions were unlikely to have led to over statement of favorable program effects on these outcome measures. The high proportions of sample members with proxy respondents reflect the frailty of the sample members. Similar rates for treatment and control groups cases with proxy respondents suggest the high use of proxy respondents has not biased the estimated program effects on survey measures.


Estimation of Granger causality through Artificial Neural Networks: applications to physiological systems and chaotic electronic oscillators.
One of the most challenging problems in the study of complex dynamical systems is to find the statistical interdependencies among the system components. Granger causality (GC) represents one of the most employed approaches, based on modeling the system dynamics with a linear vector autoregressive (VAR) model and on evaluating the information flow between two processes in terms of prediction error variances. In its most advanced setting, GC analysis is performed through a state-space (SS) representation of the VAR model that allows to compute both conditional and unconditional forms of GC by solving only one regression problem. While this problem is typically solved through Ordinary Least Square (OLS) estimation, a viable alternative is to use Artificial Neural Networks (ANNs) implemented in a simple structure with one input and one output layer and trained in a way such that the weights matrix corresponds to the matrix of VAR parameters. In this work, we introduce an ANN combined with SS models for the computation of GC. The ANN is trained through the Stochastic Gradient Descent L1 (SGD-L1) algorithm, and a cumulative penalty inspired from penalized regression is applied to the network weights to encourage sparsity. Simulating networks of coupled Gaussian systems, we show how the combination of ANNs and SGD-L1 allows to mitigate the strong reduction in accuracy of OLS identification in settings of low ratio between number of time series points and of VAR parameters. We also report how the performances in GC estimation are influenced by the number of iterations of gradient descent and by the learning rate used for training the ANN. We recommend using some specific combinations for these parameters to optimize the performance of GC estimation. Then, the performances of ANN and OLS are compared in terms of GC magnitude and statistical significance to highlight the potential of the new approach to reconstruct causal coupling strength and network topology even in challenging conditions of data paucity. The results highlight the importance of of a proper selection of regularization parameter which determines the degree of sparsity in the estimated network. Furthermore, we apply the two approaches to real data scenarios, to study the physiological network of brain and peripheral interactions in humans under different conditions of rest and mental stress, and the effects of the newly emerged concept of remote synchronization on the information exchanged in a ring of electronic oscillators. The results highlight how ANNs provide a mesoscopic description of the information exchanged in networks of multiple interacting physiological systems, preserving the most active causal interactions between cardiovascular, respiratory and brain systems. Moreover, ANNs can reconstruct the flow of directed information in a ring of oscillators whose statistical properties can be related to those of physiological networks.


Physiological parameters of gravitaxis in the flagellate Euglena gracilis obtained during a parabolic flight campaign.
The unicellular freshwater flagellate Euglena gracilis and its close relative Astasia longa show a pronounced negative gravitaxis. Previous experiments revealed that gravitaxis is most likely mediated by an active physiological mechanism in which changes of the internal calcium concentration and the membrane potential play an important role. In a recent parabolic flight experiment on board an aircraft (ESA 29th parabolic flight campaign), changes of graviorientation, membrane potential and the cytosolic calcium concentration upon changes of the acceleration (between 1 x g(n), 1.8 x g(n), microgravity) were monitored by image analysis and photometric methods using Oxonol VI (membrane potential) and Calcium Crimson (cytosolic calcium concentration). The parabolic flight maneuvers performed by the aircraft resulted in transient phases of 1.8 x g(n) (about 20 s), microgravity (about 22 s) followed by 1.8 x g(n) (about 20 s). A transient increase in the intracellular calcium concentration was detected from lower to higher accelerations (1 x g(n) to 1.8 x g(n) or microgravity to 1.8 x g(n)). Oxonol VI-labeled cells showed a signal, which indicates a depolarization during the transition from 1 x g(n) to 1.8 x g(n), a weak repolarization in microgravity followed by a rapid repolarization in the subsequent 1 x g(n) phase. The results show good coincidence with observations of recent terrestrial and space experiments.


The structure of the gamma-tubulin small complex: implications of its architecture and flexibility for microtubule nucleation.
The gamma-tubulin small complex (gamma-TuSC) is an evolutionarily conserved heterotetramer essential for microtubule nucleation. We have determined the structure of the Saccharomyces cerevisiae gamma-TuSC at 25-A resolution by electron microscopy. gamma-TuSC is Y-shaped, with an elongated body connected to two arms. Gold labeling showed that the two gamma-tubulins are located in lobes at the ends of the arms, and the relative orientations of the other gamma-TuSC components were determined by in vivo FRET. The structures of different subpopulations of gamma-TuSC indicate flexibility in the connection between a mobile arm and the rest of the complex, resulting in variation of the relative positions and orientations of the gamma-tubulins. In all of the structures, the gamma-tubulins are distinctly separated, a configuration incompatible with the microtubule lattice. The separation of the gamma-tubulins in isolated gamma-TuSC likely plays a role in suppressing its intrinsic microtubule-nucleating activity, which is relatively weak until the gamma-TuSC is incorporated into higher order complexes or localized to microtubule-organizing centers. We propose that further movement of the mobile arm is required to bring the gamma-tubulins together in microtubule-like interactions, and provide a template for microtubule growth.


A Survey of U.S Adults' Opinions about Conduct of a Nationwide Precision Medicine Initiative® Cohort Study of Genes and Environment.
A survey of a population-based sample of U.S adults was conducted to measure their attitudes about, and inform the design of the Precision Medicine Initiative's planned national cohort study. An online survey was conducted by GfK between May and June of 2015. The influence of different consent models on willingness to share data was examined by randomizing participants to one of eight consent scenarios. Of 4,777 people invited to take the survey, 2,706 responded and 2,601 (54% response rate) provided valid responses. Most respondents (79%) supported the proposed study, and 54% said they would definitely or probably participate if asked. Support for and willingness to participate in the study varied little among demographic groups; younger respondents, LGBT respondents, and those with more years of education were significantly more likely to take part if asked. The most important study incentive that the survey asked about was learning about one's own health information. Willingness to share data and samples under broad, study-by-study, menu and dynamic consent models was similar when a statement about transparency was included in the consent scenarios. Respondents were generally interested in taking part in several governance functions of the cohort study. A large majority of the U.S. adults who responded to the survey supported a large national cohort study. Levels of support for the study and willingness to participate were both consistent across most demographic groups. The opportunity to learn health information about one's self from the study appears to be a strong motivation to participate.


Use of viscoelastics post-trabeculectomy: a survey of members of the American Glaucoma Society.
American Glaucoma Society members were surveyed to determine the pattern of use of viscoelastics for anterior chamber reformation at the slit-lamp in the post-operative clinical management of patients who have undergone trabeculectomy in order to give ophthalmologists an indication of how these materials are being used by their colleagues. We surveyed 196 members of the American Glaucoma Society regarding the following; (1) whether they inject viscoelastic post-operatively at the slit-lamp as an in-office procedure, (2) the type of viscoelastic used most often, (3) the criteria for injection of viscoelastic, (4) the time to first follow-up, (5) the average number of injections, and (6) the occurrence of post-injection endophthalmitis. One hundred twenty-five (64%) of the 196 mailed surveys were answered and returned. Ninety-four (75%) of the respondents reported injecting viscoelastics in the postoperative period at the slit-lamp as an in-office procedure. Healon (60%) (Pharmacia & Upjohn Co, Kalamazoo, MI), Viscoat (17%) (Alcon, Ft. Worth, TX), and Healon GV (7%) (Pharmacia & Upjohn Co, Kalamazoo, MI) were the three most often used viscoelastics. Hypotony, iriscornea touch, and lens-cornea touch were given as criteria for injection 19%, 47%, and 88% of the time, respectively. Range of time to first follow-up was 1 hour to 7 days, with a mean time of 1 day. Range of average number of injections was 1 to 3 with a mean of 2 injections for patients requiring injection. Only one respondent reported an incidence of endophthalmitis. The use of viscoelastic materials in the postoperative trabeculectomy patient in the office at the slit-lamp for anterior chamber reformation is a prevalent practice. Healon is the most commonly used viscoelastic postoperatively and lens-corneal touch is the most common criterion for injection. The average number of injections is 2, with a mean and mode follow-up time of 1 day. Endophthalmitis is a rare complication.


Interpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference.
To estimate the minimally important difference (MID) for the Insomnia Severity Index (ISI) by examining the association of score differences of the ISI with health-related outcomes including health-related quality of life, productivity, and fatigue. Data came from a randomized, placebo-controlled clinical trial evaluating the long-term efficacy of eszopiclone for primary insomnia (N = 828). Logistic regression models were used to characterize the relationship between ISI change scores (from baseline to 6 months post-treatment) and outcomes/anchors from the SF-36 Health Survey, Work Limitations Questionnaire (WLQ), and Fatigue Severity Scale (FSS). Odds ratios were derived from the regression coefficients to calculate the probability of a given outcome being associated with different ISI change scores. Convergence between anchor- and distribution-based estimates was assessed. Higher ISI scores (indicating more severe insomnia) were significantly associated with higher probabilities of negative outcome in all models. Individuals with a 6-point score reduction in ISI scores (which corresponded to 1(1/2) standard deviations) were 48% less likely to report 'feeling worn out' (SF-36) at 6 months, 46% less likely to be 'unable to think clearly' (WLQ), and 52% less likely to report 'feeling fatigued' (FSS). Similar results were found across a broad spectrum of all selected anchors. Based on results of the study, a 6-point reduction is recommended to represent a clinically meaningful improvement in individuals with primary insomnia. Research on generalizability of the recommended MID in this study to other patient populations and other type of treatment interventions is needed.


11β-HSD1 in Human Fetal Membranes as a Potential Therapeutic Target for Preterm Birth.
Human parturition is a complex process involving interactions between the myometrium and signals derived from the placenta, fetal membranes, and fetus. Signals originating from fetal membranes are crucial components that trigger parturition, which is clearly illustrated by the labor-initiating consequence of membrane rupture. It has been recognized for a long time that among fetal tissues in late gestation the fetal membranes possess the highest capacity for cortisol regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). However, the exact role of this unique feature remains a mystery. Accumulating evidence indicates that this extra-adrenal source of cortisol may serve as an upstream signal for critical events in human parturition, including enhanced prostaglandin and estrogen synthesis as well as extracellular matrix remodeling. This may explain why such high capacity for cortisol regeneration develops in human fetal membranes at late gestation. Therefore, inhibition of 11β-HSD1 may provide a potential therapeutic target for prevention of preterm birth. This review summarizes the current understanding of the functional role of cortisol regeneration by 11β-HSD1 in human fetal membranes.


Businesses and advocacy groups create a road map for safer chemicals: the BizNGO Principles for Chemicals Policy.
This paper details how businesses and environmental organizations are collaborating to define and implement a visionary agenda for integrating safer chemicals into products, describing the challenges they confront and how they are overcoming those challenges. The framework for this assessment is the Principles for Chemicals Policy developed by the Business-NGO Working Group for Safer Chemicals and Sustainable Materials (BizNGO). The four principles--1) knowing and disclosing chemicals in products, 2) assessing and avoiding hazards, 3) committing to continuous improvement, and 4) supporting public policies and industry standards--while appearing to be straightforward, are, in fact, very complex to implement in practice. Together businesses and environmental organizations are charting a path to safer chemicals by sharing best practices, addressing technical aspects of safer chemicals substitution, and analyzing and supporting public policies that advance the rapid development and diffusion of greener chemicals in the economy.


Group-theoretic approach to the enhancement of the Fourier modal method for crossed gratings: C2 symmetry case.
A new formulation of the Fourier modal method for crossed gratings with symmetry considerations is established by using the group-theoretic approach that we have developed recently. Considering crossed gratings with the C2 symmetry (invariance after rotation about the normal of the mean grating plane through angle pi), we present in detail the construction of the new algorithm, illustrate the improved computation efficiency, and discuss its application. It is shown theoretically and numerically that when the grating is Littrow mounted and the truncated reciprocal lattice of the diffracted field also has the C2 symmetry, the maximum effective truncation number of the algorithm is doubled and the computation time is reduced by a factor of 4. The time saving factor is increased to 8 for the special case of normal incidence.


Preparation and characterisation of natamycin: gamma-cyclodextrin inclusion complex and its evaluation in vaginal mucoadhesive formulations.
Novel formulations of vaginal bioadhesive tablets were prepared where the natamycin was complexed with gamma-cyclodextrin (NT-gamma CyD) to increase the solubility and stability of NT in aqueous solutions and reduce the side effects of the drug without decreasing antimycotic activity. Favourable interactions between the NT and gamma CyD and formation of the 1:1 inclusion complex were observed. The MIC(90) of both NT alone and NT-gamma CyD complexes were below 0.0313 microg mL(-1), suggesting that complexation with gamma CyD has effectively increased the antimycotic activity of NT, thus indicating the clinical usefulness of NT-gamma CyD complexes. The sustained drug release of NT was achieved to over 8 h periods by altering the polymer component of formulations which was responsible for differences in water absorption and erosion behaviour of the tablets. Bioadhesion studies have clearly indicated that enhancement of mucoadhesion was achieved by inclusion of Carbopol 934P and by tailoring the ratio of Carbopol 934P in the formulation, a high mucoadhesion to vaginal mucosa can be achieved. Hence, the formation of complex between NT and gamma CyD and effective combination with polymers attain a bioadhesive and sustained release formulation of NT suitable for vaginal delivery and the effective treatment of Candida infections.


Immunohistochemical detection of abnormal cell proliferation in colonic mucosa of subjects with polyps.
Previous studies have shown the presence of increased proliferation in the large bowel epithelium of those at high risk of developing colon cancer. An in vitro technique for labelling large bowel mucosa with the thymidine analogue bromodeoxyuridine (Brdu) was therefore developed and its ability to distinguish differences in mucosal proliferation between subjects with colorectal adenomas and normal controls was assessed. Sigmoid biopsy specimens from 15 subjects with polyps and 15 age and sex matched controls were labelled and the incorporated Brdu visualised with an immunohistochemical technique. Mean labelling index (LI) was significantly higher in those with polyps than in controls. Differences in the pattern of labelling in colonic crypts were compared by the generation of cumulative labelling distributions. Analysis showed a significant expansion of the proliferative compartment in the colon crypts of those with polyps. It is concluded that in vitro labelling with Brdu provides a useful method for the assessment of mucosal proliferation in subjects at high risk of developing colon cancer.


Challenges to oligonucleotides-based therapeutics for Duchenne muscular dystrophy.
Antisense oligonucleotides are short nucleic acids designed to bind to specific messenger RNAs in order to modulate splicing patterns or inhibit protein translation. As such, they represent promising therapeutic tools for many disorders and have been actively developed for more than 20 years as a form of molecular medicine. Although significant progress has been made in developing these agents as drugs, they are yet not recognized as effective therapeutics and several hurdles remain to be overcome. Within the last few years, however, the prospect of successful oligonucleotides-based therapies has moved a step closer, in particular for Duchenne muscular dystrophy. Clinical trials have recently been conducted for this myopathy, where exon skipping is being used to achieve therapeutic outcomes. In this review, the recent developments and clinical trials using antisense oligonucleotides for Duchenne muscular dystrophy are discussed, with emphasis on the challenges ahead for this type of therapy, especially with regards to delivery and regulatory issues.


Processing of hormones and hormone-like substances from milk in the gastrointestinal tract of suckling rats.
Colostrum and milk contain insulin, epidermal growth factor and prostaglandins. Experiments performed in our laboratory have demonstrated that these three substances can be absorbed by the gastrointestinal tract of suckling rats in biologically active form in considerable amounts. Prostaglandins are metabolized by the gastrointestinal tract during postnatal development. There are quantitative and qualitative differences in the metabolism of orally administered prostaglandins between suckling and weanling rats. Nevertheless, a significant amount of intact prostaglandin appears in the liver of suckling rats after oral administration. Gastric administered insulin can result in hypoglycemia. In suckling rats, there is a considerable decrease in blood glucose levels, while no effect is seen in 30-day-old rats. Epidermal growth factor is processed in the gastrointestinal tract as shown by size exclusion and affinity columns and surface receptor binding. Oral administration of epidermal growth factor has several effects on gastrointestinal functions. Analysis of epidermal growth factor processing by the gastrointestinal tract demonstrated postnatal developmental differences (either during normal development, or one accelerated by steroid treatment). These studies show that the gastrointestinal tract can be influenced by orally administered hormones known to be present in milk, and that these substances can be delivered to peripheral organs of suckling animals intact.


Pseudorabies virus Us9 directs axonal sorting of viral capsids.
Pseudorabies virus (PRV) mutants lacking the Us9 gene cannot spread from presynaptic to postsynaptic neurons in the rat visual system, although retrograde spread remains unaffected. We sought to recapitulate these findings in vitro using the isolator chamber system developed in our lab for analysis of the transneuronal spread of infection. The wild-type PRV Becker strain spreads efficiently to postsynaptic neurons in vitro, whereas the Us9-null strain does not. As determined by indirect immunofluorescence, the axons of Us9-null infected neurons do not contain the glycoproteins gB and gE, suggesting that their axonal sorting is dependent on Us9. Importantly, we failed to detect viral capsids in the axons of Us9-null infected neurons. We confirmed this observation by using three different techniques: by direct fluorescence of green fluorescent protein-tagged capsids; by transmission electron microscopy; and by live-cell imaging in cultured, sympathetic neurons. This finding has broad impact on two competing models for how virus particles are trafficked inside axons during anterograde transport and redefines a role for Us9 in viral sorting and transport.


Type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea.
Pseudo-Bartter syndrome encompasses a heterogenous group of disorders similar to Bartter syndrome. Sometimes a few status may be nested, as in our case presented here. An 8-month-old boy was referred to our hospital with of intractable diarrhea, polyuria, persistent hypokalemia, abdominal distension and failure to thrive. He was born in the 34 6/7 gestational week (GW) to consanguineous parents. In the 30(th) GW polyhydramnios was verified by ultrasonography. The laboratory results showed hypokalemic-hypochloremic metabolic alkalosis, hyponatremia, and increased urinary loss of chloride, potassium and calcium. An audiogram test revealed complete sensorineural deafness. Ultrasonography revealed medullary nephrocalcinosis in both kidneys. Elevated plasma renin activity and aldosterone were found and a provisional diagnosis of type-IV neonatal Bartter syndrome was made. Treatment with indomethacin, spironolactone and additional intake of NaCl/KCl was initiated. Despite these therapies, the child's diarrhea persisted but serum potassium concentration normalized, and hypercalciuria and urine output reduced. After determining the high fecal chloride concentration, there was an immediate decompensation of the disease on indomethacin withdrawal, thus a diagnosis of type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea was considered. Indomethacin, spironolactone and supplementary therapies with NaCl/KCl were continued, which resulted in the normalization of serum electrolytes as well as his physical development, but high contents of chloride in urine and faeces and nephrocalcinosis remains unchanged during 1-year follow-up. Because of the clinical and laboratory simulations between the various diseases that lead to hypokalemic-hypochloremic metabolic alkalosis, patients must be evaluated carefully.


Virus movements on the plasma membrane support infection and transmission between cells.
How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus-host interactions upstream of infectious entry offer new perspectives for anti-viral interference.


Involvement of the PPPGHR motif in T cell activation via CD2.
Prior studies identified a segment of the CD2 cytoplasmic domain between amino acid (aa) residues 253 and 287 as important in T lymphocyte signal transduction. This region contains two repeats of the sequence motif PPPGHR, thought to form a "cage" structure involved in CD2-mediated signaling. To evaluate this segment, a series of mutant human CD2 molecules were produced by oligonucleotide-directed mutagenesis and inserted into the ovalbumin-specific, I-Ad-restricted murine T-T hybridoma 3DO54.8 using the DOL retroviral system. CD2 M1 (271-272), CD2 M2 (278-279), and CD2 M4 (264-265) mutants replaced the positively charged adjacent aa histidine and arginine (HR) in the wild-type CD2 sequence with aspartic and glutamic acid (DE) at positions 271-272, 278-279, and 264-265, respectively. In addition, a truncation mutant, CD2 M3 (268), containing only 57 of the 117 cytoplasmic aa and terminating before the second PPPGHR sequence, was generated. Stimulation of transfectants CD2 FL, CD2 M1 (271-272), and CD2 M2 (278-279) with anti-T11(2) + anti-T11(3) antibodies resulted in a rise in cytosolic-free calcium [( Ca2+]i) and subsequent interleukin 2 (IL-2) secretion. In contrast, CD2 M4 (264-265) transfectants could not be activated in either assay. Thus, alteration of histidine 264 and/or arginine 265 within the first PPPGHR motif affects the process of signal transduction via CD2, whereas identical mutations in residues at 271-272 or 278-279 were individually without effect. Consistent with these data, CD2 M3 (268) transfectants were able to generate a detectable amount of IL-2 via CD2 triggering. These data support the notion that the PPPGHR motif at aa 260-265 is important for activation of T lymphocytes via the CD2 molecule.


Geographic and facility variation in initial use of non-tunneled catheters for incident maintenance hemodialysis patients.
Non-tunneled (temporary) hemodialysis catheters (NTHCs) are the least-optimal initial vascular access for incident maintenance hemodialysis patients yet little is known about factors associated with NTHC use in this context. We sought to determine factors associated with NTHC use and examine regional and facility-level variation in NTHC use for incident maintenance hemodialysis patients. We analyzed registry data collected between January 2001 and December 2010 from 61 dialysis facilities within 12 geographic regions in Canada. Multi-level models and intra-class correlation coefficients were used to evaluate variation in NTHC use as initial hemodialysis access across facilities and geographic regions. Facility and patient characteristics associated with the lowest and highest quartiles of NTHC use were compared. During the study period, 21,052 patients initiated maintenance hemodialysis using a central venous catheter (CVC). This included 10,183 patients (48.3 %) in whom the initial CVC was a NTHC, as opposed to a tunneled CVC. Crude variation in NTHC use across facilities ranged from 3.7 to 99.4 % and across geographic regions from 32.4 to 85.1 %. In an adjusted multi-level logistic regression model, the proportion of total variation in NTHC use explained by facility-level and regional variation was 40.0 % and 34.1 %, respectively. Similar results were observed for the subgroup of patients who received greater than 12 months of pre-dialysis nephrology care. Patient-level factors associated with increased NTHC use were male gender, history of angina, pulmonary edema, COPD, hypertension, increasing distance from dialysis facility, higher serum phosphate, lower serum albumin and later calendar year. There is wide variation in NTHC use as initial vascular access for incident maintenance hemodialysis patients across facilities and geographic regions in Canada. Identifying modifiable factors that explain this variation could facilitate a reduction of NTHC use in favor of more optimal initial vascular access.


The GAP portion of Pseudomonas aeruginosa type III secreted toxin ExoS upregulates total and surface levels of wild type CFTR.
Pseudomonas aeruginosa (PA) infections account for a large percentage of fatal hospital acquired pneumonias. One of the PA Type III secreted toxin (TTST) ExoS, a bifunctional protein with N-terminal GTPase activating protein (GAP) and C-terminal ADP rybosyl transferase (ADPRT) activities, significantly contributes to PA virulence by targeting small molecular weight G-proteins (SMWGP). In this study, we have looked at one of the mechanisms by which the GAP portion of ExoS (ExoS-GAP) mediates cellular toxicity. The effects of ExoS-GAP on CFTR trafficking were studied in CFBE41o- Kir 2.2 and MDCK cell lines stably expressing CFTR using a transient transfection system. Transient transfection of ExoS-GAP increased the total and surface protein levels of mature wild type CFTR in epithelial cells stably expressing wild type (WT) CFTR. The effect of ExoS-GAP was specific to CFTR in bronchial epithelial cells since it did not affect the total protein levels of Na(+)/K(+)ATPase, another membrane protein. A point mutation in the ExoS GAP domain (R146K), known to disrupt its catalytic GAP activity, abolished the effect of ExoS-GAP on WT CFTR. Lysosomal inhibition studies with Bafilomycin A1 indicate that ExoS-GAP decreased lysosomal degradation of the mature WT CFTR with concomitant increase in the total levels of mature WT CFTR. However, ExoS-GAP did not increase the total protein levels of ∆F508CFTR. The GAP portion of the PA TTST ExoS increases the total and surface levels of wild type CFTR in vitro mammalian cell system. The effect of ExoS-GAP on WT CFTR total protein levels provides new insight into understanding the virulent pathophysiology of PA infections.


BCC-Phased PdCu Alloy as a Highly Active Electrocatalyst for Hydrogen Oxidation in Alkaline Electrolytes.
Anion-exchange membrane fuel cells hold promise to greatly reduce cost by employing nonprecious metal cathode catalysts. More efficient anode catalysts are needed, however, to improve the sluggish hydrogen oxidation reaction in alkaline electrolytes. We report that BCC-phased PdCu alloy nanoparticles, synthesized via a wet-chemistry method with a critical thermal treatment, exhibit up to 20-fold HOR improvement in both mass and specific activities, compared with the FCC-phased PdCu counterparts. HOR activity of the BCC-phased PdCu is 4 times or 2 times that of Pd/C or Pt/C, respectively, in the same alkaline electrolyte. In situ HE-XRD measurements reveal that the transformation of PdCu crystalline structure favors, at low annealing temperature (<300 °C), the formation of FCC structure. At higher annealing temperatures (300-500 °C), a BCC structure dominates the PdCu NPs. Density functional theory (DFT) computations unravel a similar H binding strength and a much stronger OH binding of the PdCu BCC surface (cf. FCC surface), both of which are simultaneously close to those of Pt surfaces. The synergistic optimization of both H and OH binding strengths is responsible for the enhancement of HOR activity on BCC-phased PdCu, which could serve as an efficient anode catalyst for anion-exchange membrane fuel cells. This work might open a new route to develop efficient HOR catalysts from the perspective of crystalline structure transformation.


Rapid susceptibility testing of Candida albicans by flow cytometry.
The emerging magnitude of human fungal infections has renewed interest in developing rapid and standardized methods for susceptibility testing. We demonstrated that susceptibility testing of Candida albicans can be accomplished rapidly by using flow cytometry. Test results were available within 8 to 24 h after C. albicans isolates were incubated with amphotericin B, itraconazole, and flucytosine. This is an improvement of 24 to 60 h in the time to availability of susceptibility test results compared to the time to availability of National Committee for Clinical Laboratory Standards-recommended broth macrodilution test results. In addition, the flow cytometric endpoints, mean channel fluorescence, and number of fluorescence-labeled C. albicans cells were easy to interpret for greater sensitivity and reliability. Flow cytometry provides a more accurate means of obtaining antifungal susceptibility test results.


Smelling excitement in the antennal lobe.
In the fly antennal lobe projection neurons receive odor information from olfactory sensory neurons and transmit it to higher brain centers. However, projection neurons respond differently to odors than sensory neurons, despite the fact that they appear to have one-to-one connectivity. Shang et al. (2007) now describe the existence of excitatory neurons within the antennal lobe that may account for some of these unexplained differences.


Influence of Type 2 Diabetes on Prevalence of Key Periodontal Pathogens, Salivary Matrix Metalloproteinases, and Bone Remodeling Markers in Sudanese Adults with and without Chronic Periodontitis.
This study compared the influence of type 2 diabetes on the occurrence of six periodontal pathogens in plaque samples of patients with and without chronic periodontitis. Levels of salivary MMP-8, MMP-9, RANKL, and OPG were also investigated. The study enrolled 31 patients with type 2 diabetes and chronic periodontitis (DM + CP), 29 with chronic periodontitis (CP), and 20 with type 2 diabetes (DM). Questionnaire-guided interviews were conducted and plaque index, bleeding on probing, and pocket depth were recorded. Polymerase chain reaction (PCR) was utilized to determine the prevalence of the bacteria. The levels of salivary molecules were determined by enzyme immunosorbent assay (ELISA). The CP group had the highest prevalence of P. gingivalis (81.5%), followed by the DM + CP (59.3%) and DM (55.0%) groups (P > 0.05). Similar trends were observed for P. intermedia and T. denticola. The prevalence of T. forsythia was 100% in both periodontitis groups compared to 90% in the DM group. There were no significant differences between the groups regarding the concentrations of MMP-8, MMP-9, or OPG. RANKL concentrations were below the detection limit. Our data show that type 2 diabetes has no significant influence on the prevalence of the investigated periodontal pathogens, or the levels of salivary MMP-8, MMP-9, and OPG.


Factors associated to infant mortality in Sub-Saharan Africa.
Half of the 10 million children who die annually in the world are from Sub-Saharan Africa (SSA). The reasons are known, but lack of will and resources avoid the development of sustainable policies. Associated factors to the high infant mortality rate (IMR) in SSA have been investigated in this research. An ecological multi-group study was designed comparing rates within SSA. The dependent variable is the IMR and health services, economic and development indicators are the independent variables. Information and data sources were WHO, World Bank, UNICEF and UNDP (1997-2007). IMR mean value is 92.2 (per 1000 live births) and a relationship with several of the factors could be observed. In the bi-variate analysis direct relationship was observed with maternal mortality rate and an inverse relationship was observed with prenatal care coverage, births assisted by skilled health personnel, gross national income per capita, per capita government expenditure on health, social security expenditure, adult literacy rate, net primary school enrolment rate, population with access to safe drinking water (in urban and rural areas) and with population with access to basic sanitation in rural areas. In the multi-variate analysis IMR had an inverse relationship with children under 5 years with diarrhoea who receive oral re-hydration, with social security expenditure as percentage of general government expenditure on health and with per capita government expenditure on health. The situation in SSA would change if their inhabitants received education and information to demand more equitable polices and better investments from their governments.


Regulatory effects of Ningdong granule on microglia-mediated neuroinflammation in a rat model of Tourette's syndrome.
Tourette's syndrome (TS) is an inherited neurologic disorder characterized by involuntary stereotyped motor and vocal tics. Its pathogenesis is still unclear and its treatment remains limited. Recent research has suggested the involvement of immune mechanisms in the pathophysiology of TS. Microglia are the brain's resident innate immune cells. They can mediate neuroinflammation and regulate brain development and homeostasis. A traditional Chinese medicine (TCM), Ningdong granule (NDG), has been found to be efficacious in the treatment of TS while causing few adverse reactions. In the current study, a rat model of 3,3'-iminodipropionitrile (IDPN)-induced TS was used to explore the regulating effects and mechanisms of NDG on microglia-mediated neuroinflammation. IDNP led to robust pathological changes and neurobehavioral complications, with activation of microglia in the striatum of rats with TS. After activation by IDNP, microglia strongly responded to this specific injury, and TNF-α, IL-6, and MCP-1 were released in the striatum and/or serum of rats with TS. Interestingly, NDG inhibited the activation of microglia and decreased the abnormal expression of TNF-α, IL-6, and MCP-1 in the striatum and/or serum of rats with TS, thus controlling tics. However, there were no significant changes in the striatum and/or serum of rats with TS after treatment with haloperidol. The anti-TS action of haloperidol might occur not through microglial activation and neuroinflammation but through the DAT system, thus controlling tics. In conclusion, microglia might play key roles in mediating neuroinflammatory responses in TS, triggering the release of TNF-α, IL-6, and MCP-1.NDG inhibited tics in rats with TS, and this mechanism may be associated with a reduction in the increased number of activated microglia and a decrease in the expression of pro-inflammatory cytokines and chemokines in the striatum and/or serum.


A functional calcium-transporting ATPase encoded by chlorella viruses.
Calcium-transporting ATPases (Ca(2+) pumps) are major players in maintaining calcium homeostasis in the cell and have been detected in all cellular organisms. Here, we report the identification of two putative Ca(2+) pumps, M535L and C785L, encoded by chlorella viruses MT325 and AR158, respectively, and the functional characterization of M535L. Phylogenetic and sequence analyses place the viral proteins in group IIB of P-type ATPases even though they lack a typical feature of this class, a calmodulin-binding domain. A Ca(2+) pump gene is present in 45 of 47 viruses tested and is transcribed during virus infection. Complementation analysis of the triple yeast mutant K616 confirmed that M535L transports calcium ions and, unusually for group IIB pumps, also manganese ions. In vitro assays show basal ATPase activity. This activity is inhibited by vanadate, but, unlike that of other Ca(2+) pumps, is not significantly stimulated by either calcium or manganese. The enzyme forms a (32)P-phosphorylated intermediate, which is inhibited by vanadate and not stimulated by the transported substrate Ca(2+), thus confirming the peculiar properties of this viral pump. To our knowledge this is the first report of a functional P-type Ca(2+)-transporting ATPase encoded by a virus.


Sunitinib efficacy against advanced renal cell carcinoma.
We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.


Regenerative endodontics: a comprehensive review.
The European Society of Endodontology and the American Association for Endodontists have released position statements and clinical considerations for regenerative endodontics. There is increasing literature on this field since the initial reports of Iwaya et al. (Dental Traumatology, 17, 2001, 185) and Banchs & Trope (Journal of Endodontics, 30, 2004, 196). Endogenous stem cells from an induced periapical bleeding and scaffolds using blood clot, platelet rich plasma or platelet-rich fibrin have been utilized in regenerative endodontics. This approach has been described as a 'paradigm shift' and considered the first treatment option for immature teeth with pulp necrosis. There are three treatment outcomes of regenerative endodontics; (i) resolution of clinical signs and symptoms; (ii) further root maturation; and (iii) return of neurogenesis. It is known that results are variable for these objectives, and true regeneration of the pulp/dentine complex is not achieved. Repair derived primarily from the periodontal and osseous tissues has been shown histologically. It is hoped that with the concept of tissue engineering, namely stem cells, scaffolds and signalling molecules, that true pulp regeneration is an achievable goal. This review discusses current knowledge as well as future directions for regenerative endodontics. Patient-centred outcomes such as tooth discolouration and possibly more appointments with the potential for adverse effects needs to be discussed with patients and parents. Based on the classification of Cvek (Endodontics and Dental Traumatology, 8, 1992, 45), it is proposed that regenerative endodontics should be considered for teeth with incomplete root formation although teeth with near or complete root formation may be more suited for conventional endodontic therapy or MTA barrier techniques. However, much is still not known about clinical and biological aspects of regenerative endodontics.


Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection.
Tumor hypoxia often directly correlates with aggressive phenotype, metastasis progression, and resistance to chemotherapy. Two transcription factors [hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha] are dramatically induced in hypoxic areas and regulate the expression of genes necessary for tumor adaptation to the conditions of low oxygen; however, the relative contribution of these factors is controversial. We used RNA interference-mediated inactivation of HIF-1alpha or HIF-2alpha followed by microarray analysis to identify genes specifically regulated by either HIF-1 or HIF-2 in hypoxia. We found that, in the MCF7 cell line, the vast majority of hypoxia-responsive genes (>80%) were dependent on the presence of HIF-1alpha. However, a small group of genes were preferentially regulated by HIF-2alpha. Promoter analysis for this group of genes revealed that all of them have putative binding sites for ETS family transcription factors, and 10 of 11 HIF-2alpha-dependent genes had at least one potential hypoxia-responsive element (HRE) in proximity to an ETS transcription factor binding site. Knockdown of ELK-1, the most often represented member of ETS family, significantly reduced hypoxic induction of the HIF-2alpha-dependent genes. Physical and functional interaction between ELK-1 and HIF-2alpha were supported by coimmunoprecipitation of these two proteins, luciferase reporter assay using CITED2 promoter, and binding of ELK-1 protein to the promoters of CITED2 and WISP2 genes in proximity to a HRE. These data suggest that the choice of the target genes by HIF-1 or HIF-2 depends on availability and cooperation of HIFs with other factors recognizing their cognate elements in the promoters.