Beyond these walls: Can psychosocial clubhouses promote the social integration of adults with serious mental illness in the community?
The study examined factors associated with community integration experiences of adults with serious mental illness who were members of psychosocial rehabilitation clubhouses in New York City. Ninety-two clubhouse members completed an online survey. The study examined relative contribution of adults' reports of individual factors (self-reported psychiatric symptoms, self-esteem), community supports (self-reported employment status and perceived family support), and the clubhouse environment (self-reported time spent in the clubhouse, clubhouse supportiveness, and practical orientation) in accounting for variation in members' reports of social integration within the clubhouse and within the larger community. Hierarchical linear regression results suggest a differential pattern of variables associated with participants' experience of social integration within the clubhouse versus outside the clubhouse with the larger non-mental-health consumers. Adults' reports of more time spent in the clubhouse and perceptions of clubhouse environment as having a more practical orientation were associated with adults' reports of greater social integration within the clubhouse. In contrast, greater self-esteem and being independently employed were associated with greater social integration outside the clubhouse. Perceived family support was associated with higher levels of social integration both within and outside the clubhouse setting. Conclusion and Implication for Practice: Greater social integration of clubhouse members both in and outside the clubhouse environment is essential in understanding community integration. Recommendations for the clubhouse model to improve community integration experiences of its members are discussed. (PsycINFO Database Record


Taking action on the social determinants of health: improving health access for the urban poor in Mongolia.
In recent years, the country of Mongolia (population 2.8 million) has experienced rapid social changes associated with economic growth, persisting socio-economic inequities and internal migration. In order to improve health access for the urban poor, the Ministry of Health developed a "Reaching Every District" strategy (RED strategy) to deliver an integrated package of key health and social services. The aim of this article is to present findings of an assessment of the implementation of the RED strategy, and, on the basis of this assessment, articulate lessons learned for equitable urban health planning. Principal methods for data collection and analysis included literature review, barrier analysis of health access and in-depth interviews and group discussions with health managers and providers. The main barriers to health access for the urban poor relate to interacting effects of poverty, unhealthy daily living environments, social vulnerability and isolation. Implementation of the RED strategy has resulted in increased health access for the urban poor, as demonstrated by health staff having reached new clients with immunization, family planning and ante-natal care services, and increased civil registrations which enable social service provision. Organizational effects have included improved partnerships for health and increased motivation of the health workforce. Important lessons learned from the early implementation of the RED strategy include the need to form strong partnerships among stakeholders at each level of the health system and in the community, as well as the need to develop a specific financing strategy to address the needs of the very poor. The diverse social context for health in an urban poor setting calls for a decentralized planning and partnership strategy, but with central level commitment towards policy guidance and financing of pro-poor urban health strategies. Lessons from Mongolia mirror other international studies which point to the need to measure and take action on the social determinants of health at the local area level in order to adequately reduce persistent inequities in health care access for the urban poor.


Sensory reliability shapes perceptual inference via two mechanisms.
To obtain a coherent percept of the environment, the brain should integrate sensory signals from common sources and segregate those from independent sources. Recent research has demonstrated that humans integrate audiovisual information during spatial localization consistent with Bayesian Causal Inference (CI). However, the decision strategies that human observers employ for implicit and explicit CI remain unclear. Further, despite the key role of sensory reliability in multisensory integration, Bayesian CI has never been evaluated across a wide range of sensory reliabilities. This psychophysics study presented participants with spatially congruent and discrepant audiovisual signals at four levels of visual reliability. Participants localized the auditory signals (implicit CI) and judged whether auditory and visual signals came from common or independent sources (explicit CI). Our results demonstrate that humans employ model averaging as a decision strategy for implicit CI; they report an auditory spatial estimate that averages the spatial estimates under the two causal structures weighted by their posterior probabilities. Likewise, they explicitly infer a common source during the common-source judgment when the posterior probability for a common source exceeds a fixed threshold of 0.5. Critically, sensory reliability shapes multisensory integration in Bayesian CI via two distinct mechanisms: First, higher sensory reliability sensitizes humans to spatial disparity and thereby sharpens their multisensory integration window. Second, sensory reliability determines the relative signal weights in multisensory integration under the assumption of a common source. In conclusion, our results demonstrate that Bayesian CI is fundamental for integrating signals of variable reliabilities.


Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.
Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2(-/-/)γc(-/-) mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing.


Mechanical properties, corrosion behavior, and cytotoxicity of biodegradable Zn/Mg multilayered composites prepared by accumulative roll bonding process.
Zinc (Zn), magnesium (Mg), and their respective alloys have attracted great attention as biodegradable bone-implant materials due to their excellent biocompatibility and biodegradability. However, the poor mechanical strength of Zn alloys and the rapid degradation rate of Mg alloys limit their clinical application. The manufacture of Zn and Mg bimetals may be a promising way to improve their mechanical and degradation properties. Here we report on Zn/Mg multilayered composites prepared via an accumulative roll bonding (ARB) process. With an increase in the number of ARB cycles, the thicknesses of the Zn layer and the Mg layer were reduced, while a large number of heterogeneous interfaces were introduced into the Zn/Mg multilayered composites. The composite samples after 14 ARB cycles showed the highest yield strength of 411±3 MPa and highest ultimate tensile strength of 501±3 MPa among all the ARB processed samples, significantly higher than those of the Zn/Zn and Mg/Mg multilayered samples. The Zn and Mg layers remained continuous in the Zn/Mg composite samples after annealing at 150 °C for 10 min, resulting in a decrease in yield strength from 411±3 MPa to 349±3 MPa but an increase in elongation from 8±1% to 28±1%. The degradation rate of the Zn/Mg multilayered composite samples in Hanks' solution was ranged from 127±18 µm/y to 6±1 µm/y. The Zn/Mg multilayered composites showed over 100% cell viability with their 25% and 12.5% extracts in relation to MG-63 cells after culturing for 3 d, indicating excellent cytocompatibility. STATEMENT OF SIGNIFICANCE: This work reports a biodegradable Zn/Mg multilayered composite prepared by accumulative roll bonding (ARB) process. The yield and ultimate tensile strength of the Zn/Mg multilayered composites were improved due to grain refinement and the introduction of a large number of heterogeneous interfaces. The composite samples after 14 ARB cycles showed the highest yield strength of 411±3 MPa and highest ultimate tensile strength of 501±3 MPa among all the ARB processed samples. The degradation rate of the Zn/Mg multilayered composite meets the required degradation rate for biodegradable bone-implant materials. The results demonstrated that it is a very promising approach to improve the strength and biocompatibility of biodegradable Zn-based alloys.


MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma.
The MHC class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-gamma in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-gamma in multiple myeloma cells, first the ability of these cells to respond to IFN-gamma was examined. RT-PCR analyses show that IFN-gammaR1, the IFN-gamma-binding chain of the IFN-gamma receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-gamma treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-gamma. RT-PCR and functional promoter analyses show that IFN-gamma upregulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to upregulate CIITA pIV and MHC II expression in response to IFN-gamma treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-gamma.


Prevalence of oromandibular dysfunction in a general population.
The prevalence of oromandibular dysfunction was studied in 735 subjects from a random sample population of 1,000 subjects aged 25 to 64 years. A diagnosis of oromandibular dysfunction was based on criteria established by the International Headache Society, as a subgroup to tension-type headache. Tenderness in pericranial or jaw muscles was not included. The most common symptoms were clenching (22%) and grinding of teeth (15%). The most common sign was irregular jaw movements on opening and closing (29%). The ratio of men to women for most symptoms and signs ranged from 2:3 to 1:3. This study serves as a base in evaluating the importance of oromandibular dysfunction as a causative factor for tension-type headache.


Risk of vertical transmission of human papillomavirus throughout pregnancy: a prospective study.
Much controversy still exists about maternal-to-infant transmission of human papillomavirus (HPV) infection, specifically about the magnitude of the risk and the route and timing of such vertical transmission. This prospective cohort study examines the risk of vertical transmission of maternal HPV in each trimester of pregnancy. One hundred fifty three healthy pregnant women were followed longitudinally throughout pregnancy and cervical swabs obtained in each trimester and postpartum for HPV detection. Cord blood, neonatal nasopharyngeal aspirates, and placental biopsies were collected at delivery. DNA isolation, polymerase chain reaction, and hybridization were performed using the GG HPV Genotyping Chip Kit (Goodgene Inc., Seoul, Korea). Detection of HPV in neonates was defined as the presence of HPV DNA in either cord blood or neonatal nasopharyngeal aspirate. HPV DNA was detected in 14%(22/153) of healthy women in the first trimester, 18%(22/124) in the second trimester, and 10%(15/153) in the third trimester; 24%(37/153) were positive for HPV DNA on at least one occasion in pregnancy. At birth, 5.2%(8/153) of neonates were HPV DNA positive. Seven of these eight infants were born to HPV-positive mothers. Placental HPV DNA was positive in 3.3%(5/152) of cases, and all five cases were from mothers with at least one HPV-positive test. Detection of HPV DNA in neonates was associated with detection of HPV in mothers during any of the three trimesters of pregnancy. HPV DNA was detected at birth in 5.2%(8/153) of neonates born to healthy women, and was associated with the detection of HPV in mothers during any of the three trimesters of pregnancy.


Longitudinal distribution of Na+ and Ca2+ channels and beta-adrenoceptors on the sarcolemmal membrane of frog cardiomyocytes.
1. The distribution of L-type Ca2+ and tetrodotoxin-sensitive Na+ channels and of beta-adrenergic receptors was examined in frog ventricular myocytes using the whole-cell patch-clamp technique and a double capillary for extracellular microperfusion. 2. Rod-shaped cells (250-300 microns long) were sealed at both ends to two patch-clamp pipettes and positioned transversally at different positions between the mouths of two microcapillaries separated by a thin wall. A combination of nifedipine (1 microM) and tetrodotoxin (0.3 microM) (blocking solution) was added to one capillary in order to inhibit macroscopic Ca2+ and Na+ currents (Ica and INa, respectively) in the part of the cell exposed to this capillary. 3. Moving the cell in 10-20 microns steps from the control capillary to the capillary containing the blocking solution induced step decreases in Ica and INa amplitudes. Complete block of both currents occurred when the entire cell was exposed to the blocking solution. 4. Each step decrease in current was due to the loss of activity of the functional Ca2+ and Na+ channels present in the slice of sarcolemmal membrane newly exposed to the blocking solution. These step current changes allowed longitudinal mapping of current density for Ca2+ and Na+ channels on the sarcolemmal membrane. 5. Addition of a submaximal concentration of isoprenaline (10 nM) to the control capillary induced a local increase in Ica which enabled examination of the distribution of functional beta-adrenergic receptors as well. 6. Our results demonstrate that Ca2+ and Na+ channels and beta-adrenergic receptors are equally and essentially uniformly distributed on the sarcolemmal of frog ventricular myocytes.


[Changes in the function of the hypothalamo-hypophyseo-adrenal system and the thymus as affected by corticotropin in guinea pigs].
Functional state of the hypothalamic-hypophyseal-adrenal system and the thymus was studied in thymic hypo- and hyperplasia of guinea pigs. It was detected that thymomegalia is accompanied by STH and prolactin hyperproduction in adeno-hypophysis, intensified lymphopoiesis (at the expense of T-lymphocytes) and the adrenal glucocorticoid function inhibition, resultant of the lowered ACTH secretion, as well as by the enhanced catecholamine and serotonin content in the hypothalamus. Reverse changes are seen in thymic hypoplasia following intramuscular ACTH injection in a dose 1 U/kg/day within 5 to 10 days.


Geographical variation in infant mortality, stillbirth and low birth weight in Northern Ireland, 1992-2002.
Improving the health of expectant mothers and reductions in health inequalities, are repeatedly prioritised in policy reports in England and Northern Ireland. Measurement of underlying rates, and geographical variation in rates, of adverse birth outcomes are tools in monitoring these priorities. Northern Ireland data on stillbirths, infant mortality and low birth weight (1992-2002) were linked to board (n=4), district council (n=26) and 1991 census wards (n=568). Underlying variations in rates were estimated at each geographical level, unadjusted and controlling for year, ward-level deprivation, settlement size and higher geographical levels. Impacts on geographical variation of individual social class, maternal age, multiple birth and smoking were assessed. There was significant variation in underlying rates of low birth weight (<2500 g) at all three geographical levels. Controlling for smoking reduced variation between wards. Geographical variation proved more robust for medium than for very low birth weight. No variation was seen between boards for other outcomes, nor between district level rates of infant mortality. Evidence was weak for variation in district rates of neonatal deaths and stillbirths, and variation in ward-level adjusted stillbirth rates was not significant. Variation in ward-level infant death rates was robust to all adjustments, with risks tripling (infant mortality) or quadrupling (neonatal mortality) between the 10th and 90th percentile. Strong evidence was found of geographical variation in infant mortality and low birth weight, unexplained by individual risk factors or by area-level deprivation. Geographical targeting or area-level interventions might look beyond deprivation scores, to other environmental and social factors.


Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial.
The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial. To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system. This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011. Apixaban therapy vs warfarin therapy. Within-trial resource use and cost were compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed. Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, -$60; 95% CI, -$2728 to $2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($53 925 per quality-adjusted life year, with 98% likelihood of meeting a $100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon. Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness. clinicaltrials.gov Identifier: NCT00412984.


[Case report: parathyroid gland adenoma].
Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone involving one or more parathyroid glands. Both familial and sporadic forms exist. Histologic examination reveals parathyroid adenoma in about 90% of patients, although it is sometimes difficult to distinguish an adenoma from a normal gland. Primary hyperparathyroidism is commonly characterized by hypercalcemia, hypophosphatemia and excessive bone resorption. This is a case report of a 52-year old female patient with toxic thyroid adenoma and a parathyroid gland adenoma. The patient underwent partial thyroidectomy as a method of choice in treatment of toxic thyroid adenoma. Two years later, clinical hyperparathyroidism caused by an adenoma of parathyroid gland has manifested and was surgically removed. In mild hypercalcemia, many patients are asymptomatic and this condition is frequently discovered accidentally during routine laboratory screening. In order to provide operative treatment efficiency in thyroid nodule cases, besides thyroid gland morphological diagnostics, it is necessary to perform a preoperative verification of parathyroid glands as well. This diagnostic approach is essential in identifying possible simultaneous occurrence of multiple diseases, such as: thyroid and adenoma of parathyroid gland, in order to diminish incorrect diagnostic estimates.


Effects of methylmercury contained in a diet mimicking the Wayana Amerindians contamination through fish consumption: mercury accumulation, metallothionein induction, gene expression variations, and role of the chemokine CCL2.
Methylmercury (MeHg) is a potent neurotoxin, and human beings are mainly exposed to this pollutant through fish consumption. We addressed the question of whether a diet mimicking the fish consumption of Wayanas Amerindians from French Guiana could result in observable adverse effects in mice. Wayanas adult men are subjected to a mean mercurial dose of 7 g Hg/week/kg of body weight. We decided to supplement a vegetarian-based mice diet with 0.1% of lyophilized Hoplias aimara fish, which Wayanas are fond of and equivalent to the same dose as that afflicting the Wayanas Amerindians. Total mercury contents were 1.4 ± 0.2 and 5.4 ± 0.5 ng Hg/g of food pellets for the control and aimara diets, respectively. After 14 months of exposure, the body parts and tissues displaying the highest mercury concentration on a dry weight (dw) basis were hair (733 ng/g) and kidney (511 ng/g), followed by the liver (77 ng/g). Surprisingly, despite the fact that MeHg is a neurotoxic compound, the brain accumulated low levels of mercury (35 ng/g in the cortex). The metallothionein (MT) protein concentration only increased in those tissues (kidney, muscles) in which MeHg demethylation had occurred. This can be taken as a molecular sign of divalent mercurial contamination since only Hg(2+) has been reported yet to induce MT accumulation in contaminated tissues. The suppression of the synthesis of the chemokine CCL2 in the corresponding knockout (KO) mice resulted in important changes in gene expression patterns in the liver and brain. After three months of exposure to an aimara-containing diet, eight of 10 genes selected (Sdhb, Cytb, Cox1, Sod1, Sod2, Mt2, Mdr1a and Bax) were repressed in wild-type mice liver whereas none presented a differential expression in KO Ccl2(-/-) mice. In the wild-type mice brain, six of 12 genes selected (Cytb, Cox1, Sod1, Sod2, Mdr1a and Bax) presented a stimulated expression, whereas all remained at the basal level of expression in KO Ccl2(-/-) mice. In the liver of aimara-fed mice, histological alterations were observed for an accumulated mercury concentration as low as 32 ng/g, dw, and metal deposits were observed within the cytoplasm of hepatic cells.


Dealing with spatial misalignment to model the relationship between deprivation and life expectancy: a model-based geostatistical approach.
BACKGROUND : Life expectancy at birth (LEB), one of the main indicators of human longevity, has often been used to characterise the health status of a population. Understanding its relationships with the deprivation is key to develop policies and evaluate interventions that are aimed at reducing health inequalities. However, methodological challenges in the analysis of LEB data arise from the fact that different Government agencies often provide spatially aggregated information on LEB and the index of multiple deprivation (IMD) at different spatial scales. Our objective is to develop a geostatistical framework that, unlike existing methods of inference, allows to carry out spatially continuous prediction while dealing with spatial misalignment of the areal-level data. METHODS : We developed a model-based geostatistical approach for the joint analysis of LEB and IMD, when these are available over different partitions of the study region. We model the spatial correlation in LEB and IMD across the areal units using inter-point distances based on a regular grid covering the whole of the study area. The advantages and strengths of the new methodology are illustrated through an analysis of LEB and IMD data from the Liverpool district council. RESULTS : We found that the effect of IMD on LEB is stronger in males than in females, explaining about 63.35% of the spatial variation in LEB in the former group and 38.92% in the latter. We also estimate that LEB is about 8.5 years lower between the most and least deprived area of Liverpool for men, and 7.1 years for women. Finally, we find that LEB, both in males and females, is at least 80% likely to be above the England wide average only in some areas falling in the electoral wards of Childwall, Woolton and Church. CONCLUSION : The novel model-based geostatistical framework provides a feasible solution to the spatial misalignment problem. More importantly, the proposed methodology has the following advantages over existing methods used model LEB: (1) it can deliver spatially continuous inferences using spatially aggregated data; (2) it can be applied to any form of misalignment with information provided at a range of spatial scales, from areal-level to pixel-level.


A multiscale random field model for Bayesian image segmentation.
Many approaches to Bayesian image segmentation have used maximum a posteriori (MAP) estimation in conjunction with Markov random fields (MRF). Although this approach performs well, it has a number of disadvantages. In particular, exact MAP estimates cannot be computed, approximate MAP estimates are computationally expensive to compute, and unsupervised parameter estimation of the MRF is difficult. The authors propose a new approach to Bayesian image segmentation that directly addresses these problems. The new method replaces the MRF model with a novel multiscale random field (MSRF) and replaces the MAP estimator with a sequential MAP (SMAP) estimator derived from a novel estimation criteria. Together, the proposed estimator and model result in a segmentation algorithm that is not iterative and can be computed in time proportional to MN where M is the number of classes and N is the number of pixels. The also develop a computationally efficient method for unsupervised estimation of model parameters. Simulations on synthetic images indicate that the new algorithm performs better and requires much less computation than MAP estimation using simulated annealing. The algorithm is also found to improve classification accuracy when applied to the segmentation of multispectral remotely sensed images with ground truth data.


In patients with HIV-infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double-blind, placebo controlled trial.
Chromium is an essential micronutrient; chromium deficiency has been reported to cause insulin resistance, hyperglycemia and hyperlipidemia. The aim was to investigate the effect of chromium supplementation on insulin-resistance, other metabolic abnormalities, and body composition in people living with HIV. This was a randomized, double-blind, placebo-controlled trial. Fifty-two HIV-positive subjects with elevated glucose, lipids, or evidence of body fat redistribution, and who had insulin-resistance based on the calculation of homeostasis model of assessment (HOMA-IR > or = 2.5) were assessed. Subjects who were on insulin or hypoglycemic medications were excluded. Subjects were randomized to receive either 400 microg/day chromium-nicotinate or placebo for 16 weeks. Forty-six subjects, 23 in each group, completed the study. Fasting blood insulin, glucose, lipid profile and body composition were measured before and after intervention. Chromium was tolerated without side effects and resulted in a significant decrease in HOMA-IR (median (IQR) (pre:4.09 (3.02-8.79); post: 3.66 (2.40-5.46), p=0.004), insulin (pre: 102 (85-226); post: 99 (59-131) pmol/L, p=0.003), triglycerides, total body fat mass (mean+/-SEM) (pre: 17.3+/-1.7; post: 16.3+/-1.7 kg; p=0.002) and trunk fat mass (pre: 23.8+/-1.9; post: 22.7+/-2.0 %; p=0.008). Blood glucose, C-peptide, total, HDL and LDL cholesterol, and hemoglobin A1c remained unchanged. Biochemical parameters did not change in the placebo group except for LDL cholesterol which increased significantly. Body weight and medication profile remained stable throughout the study for both groups. In summary, chromium improved insulin resistance, metabolic abnormalities, and body composition in HIV+ patients. This suggests that chromium supplements alleviate some of the antiretroviral-associated metabolic abnormalities.


Direct investigation of cell contraction signal networks by light-based perturbation methods.
Cell contraction plays an important role in many physiological and pathophysiological processes. This includes functions in skeletal, heart, and smooth muscle cells, which lead to highly coordinated contractions of multicellular assemblies, and functions in non-muscle cells, which are often highly localized in subcellular regions and transient in time. While the regulatory processes that control cell contraction in muscle cells are well understood, much less is known about cell contraction in non-muscle cells. In this review, we focus on the mechanisms that control cell contraction in space and time in non-muscle cells, and how they can be investigated by light-based methods. The review particularly focusses on signal networks and cytoskeletal components that together control subcellular contraction patterns to perform functions on the level of cells and tissues, such as directional migration and multicellular rearrangements during development. Key features of light-based methods that enable highly local and fast perturbations are highlighted, and how experimental strategies can capitalize on these features to uncover causal relationships in the complex signal networks that control cell contraction.


Sequential activation of murine mononuclear phagocytes for tumor cytolysis: differential expression of markers by macrophages in the several stages of development.
Murine mononuclear phagocytes in various stages of activation were elicited in vivo or induced in vitro. The cytolytic competence of each type of macrophage, before and after treatment with traces of endotoxin, was quantified. Populations of responsive, primed, and activated macrophages, but not resident macrophages, expressed five markers that have been reported to characterize inflammatory macrophages: increased spreading, increased phagocytosis via Fc and C3 receptors, increased secretion of plasminogen activator, and decreased content of the ectoenzyme 5' nucleotidase. Primed macrophages secreted cytolytic protease (CP) when pulsed with traces of endotoxin; the resident and responsive macrophages did not. The primed macrophages bound tumor cells to a considerable degree; the resident and responsive macrophages did not. The cytolytically activated macrophages bound tumor cells well and secreted lytic protease spontaneously. The capacity for augmented, selective binding of tumor cells is apparently induced in only one step by application of lymphokine(s). The capacity for secreting CP, however, is regulated in two steps; initial priming signals--lymphokine(s)--prepare the macrophages for secretion, and a second signal, such as endotoxin or endotoxin plus tumor cells, triggers the actual release of CP.


Evaluating the profile of selected cytokines in patients with food allergy and chronic gastritis.
Evaluating the profile of selected cytokines in patients with food allergy and chronic gastritis. Cytokines are produced by many cells and they play a role of mediators in the development of local and systemic inflammatory reaction. The aim of the study was to determine serum concentrations of IL-4, IL-5, IL-8, TNF alpha in patients with chronic gastritis and food allergy, who had been infected with H. pylori. The study was conducted on patients with atopic diathesis, who were allergic to certain foods. The study group consisted of 71 patients, including 42 females aged 16-54 years (mean age 35.5 years) and 29 males aged 18-60 years (mean age 36.2 years). One control group was formed of 40 non-atopic patients aged 18-56 years (mean age 34.8 years), suffering from chronic gastritis. The other control group consisted of 30 subjects with the diagnosis of functional dyspepsia. Serum levels of selected cytokines were determined with the kits manufactured by ENDOGEN (Cambridge MA, USA) using enzyme immunoassay ELISA. The concentrations of parameters were determined in two tests and they were given as mean value. Mean serum Il-4 level in atopic patients was 27.85 pg/ml, while it was 13.26 pg/ml in non-atopic subjects with chronic gastritis and 4.3 pg/ml in patients with functional dyspepsia. The concentration of IL-5 ranged between 0 and 111.3 pg/ml (mean value: 7.43 pg/ml) in subjects with food allergy. Comparative analysis of IL-4 and IL-5 concentrations in atopic patients and in control subjects showed the presence of statistically significant differences (p < 0.001). The remaining cytokines, i.e. IL-8 and TNF alpha showed a significant increase in serum levels in patients chronic gastritis when compared to the subjects with functional dyspepsia, without inflammatory changes. Chronic exposure of the patients with food allergy to a given food allergen makes the levels of IL-4 and IL-5 rise. In atopic subjects with chronic gastritis and H. pylori infection, the increase in IL-4, IL-5, IL-8 and TNF alpha levels suggests that both infectious and allergic factors play an important role in the pathogenesis of inflammation.


Highly informative ancient DNA 'snippets' for New Zealand moa.
Analysis of ancient DNA has provided invaluable information on past ecologies, ancient populations, and extinct species. We used a short snippet of highly variable mitochondrial control region sequence from New Zealand's moa to characterise a large number of bones previously intractable to DNA analysis as well as bone fragments from swamps to gain information about the haplotype diversity and phylogeography that existed in five moa species. By targeting such 'snippets', we show that moa populations differed substantially in geographic structure that is likely to be related to population mobility and history. We show that populations of Pachyornis geranoides, Dinornis novaezealandiae, and Dinornis robustus were highly structured and some appear to have occupied the same geographic location for hundreds of thousands of years. In contrast, populations of the moa Anomalopteryx didiformis and Euryapteryx curtus were widespread, with specific populations of the latter occupying both the North and South Islands of New Zealand. We further show that for a specific area, in this case a North Island swamp, complete haplotype diversity and even sex can be recovered from collections of small, often discarded, bone fragments. Short highly variable mitochondrial 'snippets' allow successful typing of environmentally damaged and fragmented skeletal material, and can provide useful information about ancient population diversity and structure without the need to sample valuable, whole bones often held by museums.


Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.


Surface membrane glycoproteins of wild-type and differentiation-inducer-resistant HL-60 cells.
Surface membrane glycoproteins (SMGs) of cells from the parental wild-type HL-60 cell line and from three sublines variably cross-resistant to the granulocyte differentiation-inducing effects of retinoic acid (RA), dimethylsulfoxide (DMSO), and certain purine bases (6-thioguanine [6TG] or hypoxanthine) were studied by one-dimensional and two-dimensional gel electrophoresis. After both oligosaccharide (periodate/borotritide) and peptide (1,3,4,6-tetrachloro-3 alpha, 6 alpha-diphenylglycouril) ectolabeling procedures, striking common changes were noted in the gel electrophoretic patterns of the SMGs from the RA- and 6TG-resistant sublines compared to those from the wild-type HL-60 line or the DMSO-resistant subline. Most prominently, this included the presence in the RA- and 6TG-resistant cells of an apparent high molecular weight acidic glycoprotein(s) (mol wt, 200 to 285 kilodaltons [kD]; isoelectric point range [pl], 4.5 to 6.0) not observed in the wild-type or DMSO-resistant cells and, conversely, the presence of a lower molecular weight glycoprotein(s) (mol wt, 120 to 165 kD; pl, 4.2 to 5.9) in the wild-type and DMSO-resistant cells, which was absent or much reduced in the RA- and 6TG-resistant cells. These acidic SMGs did not change as a function of the induction of granulocyte differentiation. However, some other more basic SMGs varied as a function of granulocyte differentiation in both the wild-type and differentiation inducer-resistant sublines, including the loss of the transferrin receptor and the gain of a mol wt 55- to 60-kD neutrophil-associated protein. In the context of previously reported information, these results indicate (1) that the overall pattern of SMG changes in the RA- and 6TG-resistant cells closely resembles that associated with multidrug (pleiotropic) resistance to cytotoxic agents in a variety of mammalian cells; (2) that the RA/6TG resistance-associated SMG changes are not granulocyte differentiation stage-specific; and (3) that either the RA/6TG resistance-associated SMG changes are not related to the resistance mechanism or they are involved in the resistance/cross-resistance mechanism(s) for RA/purine bases but not for DMSO.


Burkholderia symbiotica sp. nov., isolated from root nodules of Mimosa spp. native to north-east Brazil.
Four strains, designated JPY-345(T), JPY-347, JPY-366 and JPY-581, were isolated from nitrogen-fixing nodules on the roots of two species of Mimosa, Mimosa cordistipula and Mimosa misera, that are native to North East Brazil, and their taxonomic positions were investigated by using a polyphasic approach. All four strains grew at 15-43 °C (optimum 35 °C), at pH 4-7 (optimum pH 5) and with 0-2 % (w/v) NaCl (optimum 0 % NaCl). On the basis of 16S rRNA gene sequence analysis, strain JPY-345(T) showed 97.3 % sequence similarity to the closest related species Burkholderia soli GP25-8(T), 97.3 % sequence similarity to Burkholderia caryophylli ATCC25418(T) and 97.1 % sequence similarity to Burkholderia kururiensis KP23(T). The predominant fatty acids of the strains were C(18 : 1)ω7c (36.1 %), C(16 : 0) (19.8 %) and summed feature 3, comprising C(16 : 1)ω7c and/or C(16 : 1)ω6c (11.5 %). The major isoprenoid quinone was Q-8 and the DNA G+C content of the strains was 64.2-65.7 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and several uncharacterized aminophospholipids and phospholipids. DNA-DNA hybridizations between the novel strain and recognized species of the genus Burkholderia yielded relatedness values of <51.8 %. On the basis of 16S rRNA and recA gene sequence similarities and chemotaxonomic and phenotypic data, the four strains represent a novel species in the genus Burkholderia, for which the name Burkholderia symbiotica sp. nov. is proposed. The type strain is JPY-345(T) (= LMG 26032(T) = BCRC 80258(T) = KCTC 23309(T)).


Studies on the release of gonadotrophins during the superfusion of isolated rat pituitaries in a continuous flow system.
A continuous flow system has been developed to study the endocrine functions of isolated organs. The procedure has been used to investigate the effect of a synthetic gonadotrophin-releasing hormone (Gn-RH) upon the anterior pituitary gland of the adult male rat. A Radiometer blood gas/pH analyser was used to monitor the pH and partial pressures of oxygen and carbon dioxide in the perfusion medium. A series of six experiments with four pituitaries per flask established that the rate of gonadotrophin release under basal conditions was 646 +/- 301 (S.D.) ng LH/ml and 404 +/- 124 (S.D.) ng FSH/ml. The duration and intensity of the response to Gn-RH was assessed by measuring the areas under the curves according to the trapezoidal rule. A significant increase in the release of FSH and LH was obtained by the administration of 250 ng Gn-RH/ml medium, and dose-response curves were produced for up to 10 mug/ml.


Cyproheptadine enhances the I(K) of mouse cortical neurons through sigma-1 receptor-mediated intracellular signal pathway.
Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 α-subunit to address whether CPH modify neural voltage-gated K(+) channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I(K) by reducing the activity of protein kinas A (PKA). Inhibition of G(i) eliminated the CPH-induced effect on both the I(K) and PKA. Blocking of 5-HT-, M-, D(2)-, H(1)- or H(2)-type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I(K). Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I(K). On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I(K). A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the α-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I(K) by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/G(i)-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I(K), which is independent of histamine H(1) and serotonin receptors.


Inhibition of CD38 with the Thiazoloquin(az)olin(on)e 78c Protects the Heart against Postischemic Injury.
Inhibition of and genetic deletion of the NAD(P)+ hydrolase [NAD(P)ase] CD38 have been shown to protect against ischemia/reperfusion (I/R) injury in rat and mouse hearts. CD38 has been shown to enhance salvage of NADP(H), which in turn prevents impairment of endothelial nitric oxide synthase function, a hallmark of endothelial dysfunction. Despite growing evidence for a role of CD38 in postischemic injury, until recently there had been a lack of potent CD38 inhibitors. Recently, a new class of thiazoloquin(az)olin(on)e compounds were identified as highly potent and specific CD38 inhibitors. Herein, we investigate the ability of one of these compounds, 78c, to inhibit CD38 and protect the heart in an ex vivo model of myocardial I/R injury. The potency and mechanism of CD38 inhibition by 78c was assessed in vitro using recombinant CD38. The dose-dependent tissue uptake of 78c in isolated mouse hearts was determined, and high tissue permeability of 78c was observed when delivered in perfusate. Treatment of hearts with 78c was protective against both postischemic endothelial and cardiac myocyte injury, with preserved nitric oxide synthase-dependent vasodilatory and contractile function, respectively. Myocardial infarction was also significantly decreased in 78c-treated hearts, with preserved levels of high-energy phosphates. Protective effects peaked at 10 μM treatment, and similar protection without toxicity was seen at 5-fold higher doses. Overall, 78c was shown to be a potent and biologically active CD38 inhibitor with favorable tissue uptake and marked protective effects against I/R injury with enhanced preservation of contractile function, coronary flow, and decreased infarction.


Comparative analysis of the diagnostic performance of six major Echinococcus granulosus antigens assessed in a double-blind, randomized multicenter study.
The serodiagnosis of hydatid disease is a valuable instrument for clinical diagnosis and epidemiological surveillance of high-risk populations. In the past decade a wealth of reports on the diagnostic performance of numerous antigens have been produced. However, their diagnostic value has been estimated under different conditions, using different serum collection, therefore precluding their direct comparison. Here we report an unbiased comparison of the same batch of six major E. granulosus antigens, namely, hydatid cyst fluid (HCF), native antigen B (AgB), two recombinant AgB subunits, an AgB-derived synthetic peptide, and recombinant cytosolic malate dehydrogenase from E. granulosus (EgMDH), against the same serum collection. The double-blind analysis was performed using a standardized protocol and receiver operating characteristic (ROC) data analysis by a network of six South American laboratories. High intercenter reproducibility was attained, and the intralaboratory analysis allowed the comparative ranking of the antigen panel. HCF, AgB, and its AgB8/1 subunit exhibited equivalent diagnostic efficiencies, 81.4% +/- 0.5%, 81.3% +/- 0.6%, and 81.9% +/- 2.0%, respectively; with a more favorable balance toward specificity in the case of the last antigen. The diagnostic efficiencies for the other three antigens were 76.8% +/- 6.8%, 69.1% +/- 2.7%, and 66.8% +/- 2.1%, for the peptide, the AgB8/2 subunit, and the EgMDH, respectively. The study also included an analysis of batch-to-batch variation in the diagnostic performance of different HCF regional preparations. Based on these results, a suggested recommendation on the use of these antigens was drawn.


Understanding desisting and persisting forms of delinquency: the unique contributions of disruptive behavior disorders and interpersonal callousness.
While associations between conduct disorder (CD), oppositional defiant disorder (ODD), attention deficit hyperactivity disorder (ADHD), and interpersonal callousness (IC) symptoms and delinquency onset are well established, less is known about whether these characteristics differentiate desisting and persisting delinquency. The current study examined whether childhood and adolescent CD, ODD, ADHD, and IC symptoms uniquely distinguished boys who exhibited persisting versus desisting delinquency from adolescence into adulthood. Participants were 503 boys (57% African American) repeatedly assessed from ages 7 to 25. Associations between childhood and adolescent CD, ODD, ADHD, and IC symptoms and desisting and persisting delinquency were examined independently and after controlling for their co-occurrence and multiple covariates. Conduct disorder and IC symptoms in childhood and adolescence were higher among boys whose delinquency persisted into adulthood relative to those boys whose delinquency desisted across time. After controlling for the overlap between symptoms of ADHD, ODD, CD and IC, only adolescent CD and IC symptoms emerged as unique predictors of the differentiation between persisters and desisters. Moreover, adolescent CD and IC symptoms continued to contribute unique variance even after childhood levels of these characteristics were accounted for. Boys with elevated levels of CD and IC symptoms in childhood and adolescence are at risk for exhibiting a pattern of delinquency that persists from adolescence into adulthood. Intervention efforts designed to prevent chronic delinquency should target youth with co-occurring CD and IC symptoms in childhood and adolescence.


Reactivation of latent herpes simplex virus from dissociated identified dorsal root ganglion cells in culture.
Herpes simplex virus (HSV) types 1 and 2 reactivate from dissociated cultured dorsal root ganglia of latently infected mice. The neurons in culture were identified morphologically and by using the specific anti-neuronal monoclonal antibody A2B5. HSV antigen expression during reactivation was first seen in neurons on day 3 after dissociation, and infectious virus was released subsequently. Approximately 0.4% of neurons released infectious virus. The presence of neutralizing antibody to HSV did not modify the reactivation process. After infection of mouse neuronal cultures in vitro with HSV, cytopathic effect and viral antigen expression appeared within 18 h predominantly in fibroblastic cells.


The heterochronic gene Lin28 regulates amphibian metamorphosis through disturbance of thyroid hormone function.
Metamorphosis is a classic example of developmental transition, which involves important morphological and physiological changes that prepare the organism for the adult life. It has been very well established that amphibian metamorphosis is mainly controlled by Thyroid Hormone (TH). Here, we show that the heterochronic gene Lin28 is downregulated during Xenopus laevis metamorphosis. Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes. The delay in metamorphosis is rescued by incubation with exogenous TH, indicating that Lin28 works upstream or parallel to TH. High-throughput analyses performed before any delay on metamorphosis or change in TH signaling showed that overexpression of Lin28 reduces transcript levels of several hormones secreted by the pituitary, including the Thyroid-Stimulating Hormone (TSH), and regulates the expression of proteins involved in TH transport, metabolism and signaling, showing that Lin28 disrupts TH function at different levels. Our data demonstrates that the role of Lin28 in controlling developmental transitions is evolutionary conserved and establishes a functional interaction between Lin28 and thyroid hormone function introducing a new regulatory step in perinatal development with implications for our understanding of endocrine disorders.


Estrogen receptor alpha-mediated mitochondrial damage in intrahepatic bile duct epithelial cells leading to the pathogenesis of primary biliary cholangitis.
This study investigated the effects of estrogen and estrogen receptor alpha (ERα) on the pathogenesis of primary biliary cholangitis (PBC) in human intrahepatic bile duct epithelial cells (HiBECs). The researchers measured serum levels of ERα, oxidative stress indicators, and cytokines in PBC patients and healthy controls. They examined the expression of ERα, pyruvate dehydrogenase complex E2-component (PDC-E2), and apoptosis-related proteins in the small bile ducts. In vitro experiments with HiBECs showed that estrogen had a dual effect on cell viability, increasing it at low concentrations but reducing it at higher concentrations. ERα activation led to mitochondrial damage, apoptosis, and upregulation of ERα and PDC-E2 expression. These findings suggest that the high expression of ERα in the bile ducts contributes to mitochondrial damage, inflammation, and apoptosis in PBC. The study highlights ERα as a potential target for understanding and treating estrogen-mediated PBC pathogenesis.


Pediatric Thromboprophylaxis of Large Coronary Artery Aneurysm Using Rivaroxaban.
Giant or large coronary artery aneurysms (CAA) are rare in children, most often secondary to Kawasaki disease, and anticoagulation is recommended to prevent thromboembolism. There are no published pediatric reports on the use of a direct oral anticoagulant for this indication. We describe the anticoagulation management of an 8-year-old boy with a dilated right CAA secondary to Kawasaki disease that has remained stable on rivaroxaban and aspirin, following bleeding complications on enoxaparin and challenges on warfarin. The use of rivaroxaban appears to be safe and effective in the prevention of thrombosis in a pediatric patient with CAA.


Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae in an urban public hospital pregnancy termination clinic.
This study is a follow-up observational study to assess the prevalence of chlamydia (CT) and gonorrhea (GC) among women who undergo a first-trimester surgical termination in a large public, urban hospital-based termination clinic, and to compare the rates to previously published data. We conducted a retrospective chart review on 4197 patients who underwent CT and GC testing before an elective, first-trimester surgical termination between 1 June 2014 and 31 May 2015. The prevalence rates were calculated and compared by chi square tests to previously published data from 1 January 2006 to 30 June 2006 from the same publicly-funded pregnancy termination clinic. Our study population comprised mostly of African Americans (86.8%), and more than half were aged less than 25 years. The overall prevalence of CT in our population was 9.6%, which was significantly different to the prevalence of 11.4% in 2006 ( p value = 0.03). The overall prevalence of GC in our population was 1.9%, which was not significantly different to the prevalence of 2.6% in 2006. To conclude, this study demonstrates the high prevalence rate of CT-positive and GC-positive patients in our publicly-funded pregnancy termination clinic. The prevalence of infection with CT and GC in our study is higher than in other family planning clinics. Regular screening of all patients who undergo induced termination in pregnancy termination clinics can provide a valuable opportunity for physicians to counsel patients about sexually transmitted infection prevention and treatment prior to the procedure or distribution of medications.


Managing Perceived Loneliness and Social-Isolation Levels for Older Adults: A Survey with Focus on Wearables-Based Solutions.
As an inevitable process, the number of older adults is increasing in many countries worldwide. Two of the main problems that society is being confronted with more and more, in this respect, are the inter-related aspects of feelings of loneliness and social isolation among older adults. In particular, the ongoing COVID-19 crisis and its associated restrictions have exacerbated the loneliness and social-isolation problems. This paper is first and foremost a comprehensive survey of loneliness monitoring and management solutions, from the multidisciplinary perspective of technology, gerontology, socio-psychology, and urban built environment. In addition, our paper also investigates machine learning-based technological solutions with wearable-sensor data, suitable to measure, monitor, manage, and/or diminish the levels of loneliness and social isolation, when one also considers the constraints and characteristics coming from social science, gerontology, and architecture/urban built environments points of view. Compared to the existing state of the art, our work is unique from the cross-disciplinary point of view, because our authors' team combines the expertise from four distinct domains, i.e., gerontology, social psychology, architecture, and wireless technology in addressing the two inter-related problems of loneliness and social isolation in older adults. This work combines a cross-disciplinary survey of the literature in the four aforementioned domains with a proposed wearable-based technological solution, introduced first as a generic framework and, then, exemplified through a simple proof of concept with dummy data. As the main findings, we provide a comprehensive view on challenges and solutions in utilizing various technologies, particularly those carried by users, also known as wearables, to measure, manage, and/or diminish the social isolation and the perceived loneliness among older adults. In addition, we also summarize the identified solutions which can be used for measuring and monitoring various loneliness- and social isolation-related metrics, and we present and validate, through a simple proof-of-concept mechanism, an approach based on machine learning for predicting and estimating loneliness levels. Open research issues in this field are also discussed.


Cadaveric & living organ donation. Natural limitations. Possible solutions. Singapore experience.
Singapore is a country with different cultures and beliefs. Over the last thirty eight years since independance, it has blossomed close to being a developed nation. Having performed the first cadaver donor renal transplantation in 1970, there has been a tremendous amount of health literacy injected into the Singaporeans, with the able support of the National Kidney Foundation. Never ending waiting list for organ donation has facilitated a march of events from Volunatary Organ Pledging under the Medical Therapy, Education and Research Act to passing the Human Organ Transplant Act to extension of the presumed consent law to include Heart, Liver and Cornea and non-accidental brain deaths. In the years to come, Singapore will certainly see an increase in the number of organ transplantations both Cadaveric and Living related.


A randomized trial of contact force in atrial flutter ablation.
Contact force (CF) sensing has emerged as a tool to guide and improve outcomes for catheter ablation (CA) for cardiac arrhythmias. The clinical benefit on patient outcomes remains unknown. To study whether CF-guided CA for typical atrial flutter (AFL) is superior to CA not guided by CF. In a double-blinded controlled superiority trial, we randomized patients 1:1 to receive CA for typical AFL guided by CF (intervention group) or blinded to CF (control group). In the intervention group, a specific value of the lesion size index (LSI), estimating ablation lesions size was targeted for each ablation lesion. Patients underwent electrophysiological study (EPS) after 3 months to assess occurrence of the primary endpoint of re-conduction across the cavo-tricuspid isthmus (CTI). We included 156 patients with typical AFL, median age was 68 [interquartile range (IQR) 61-74] years and 120 (77%) patients were male. At index procedure median LSI was higher in the intervention group [6.4 (IQR 5.1-7) vs. 5.6 (IQR 4.5-6.9), P < 0.0001]. After 3 months, 126 patients (58 in intervention group) underwent EPS for primary endpoint assessment. Thirty (24%) patients had CTI re-conduction, distributed with 15 patients in each treatment group (P = 0.62). We observed no difference between treatment groups with regard to fluoroscopy, ablation, or procedure times, nor peri-procedural complications. Contact force-guided ablation does not reduce re-conduction across the CTI after 3 months, nor does CF-guided ablation shorten fluoroscopy, ablation, or total procedure times.


[Iron-deficiency anemia: PAHO/WHO strategies to fight it].
Iron deficiency anemia is among the greatest nutritional problems in the world. Although its etiology is understood and intervention at low cost is available, the problem persists. The present review begins with a general estimate of the dimensions of the problem. It suggests the necessary elements for the design, implementation, and measurement of the impact of iron supplementing and fortification as the most effective forms to intervene and diminish iron deficiency anemia. Several preliminary steps are proposed previous to the preparation of a project and several recommendations are made to be included in a project for fortification and iron supplementing. A list of complementary activities offered by PAHO/WHO as part of the package of technical cooperation is included.


Macromolecular prodrugs for controlled delivery of ribavirin.
Ribavirin (RBV)-containing polymers are synthesized based on poly(N-vinylpyrrolidone) and poly(acrylic acid), two polymers with extensive characterization in biomedicine. The copolymers are shown to exhibit a minor to negligible degree of association with erythrocytes, thus effectively eliminating the origin of the main side effects of RBV. The therapeutic benefit of macromolecular RBV prodrugs is illustrated by matched efficacy in suppressing production of nitric oxide by stimulated cultured macrophages as compared to pristine RBV with no associated cytotoxicity, which is in stark contrast to an RBV-based treatment which results in a significant decrease in cell viability. These results contribute to the development of antiviral polymer therapeutics and delivery of RBV in particular.


Enhancing Provider Mental Health Screening in Primary Care: A Quality Improvement Project.
Background: Depression and anxiety occur in 7.8% and 19.1% of the US population, respectively. About half of those patients are diagnosed in primary care. Objective: The purpose of this quality improvement project was to improve the screening and diagnosing of anxiety and/or depression among adult patients at a primary care clinic by implementing an evidence-based mental health screening interview technique. Methods: The team implemented a mental health screening interview technique that incorporates background, affect, trouble, handling, and empathy and motivational interviewing techniques in addition to self-report surveys. Pre- and post-intervention surveys were conducted to assess providers' perceptions of the new interview technique. ICD-10 code data were gathered to assess the effectiveness of the new mental health screening interview technique. Results: The number of documented diagnoses of single-episode major depressive disorder decreased by 18%, recurrent major depressive disorder increased by 34%, and anxiety disorders increased by 3%. There were more favorable provider perceptions of the new screening interview technique versus the traditional screening method. Conclusions: The results show an improvement in provider comfort and providers preferred the new mental health screening when using an evidence-based mental health screening interview technique. Implications for nursing: The results show the potential benefits of using a structured mental health interview with self-report screening tools when diagnosing anxiety and depression in primary care.


Hantaviruses.
Since the recognition of the hantavirus pulmonary syndrome (HPS) in the USA in 1993, interest in hantavirus diseases has intensified worldwide. It is clear that hantaviruses have been historically responsible for a variety of human illnesses. Hantaviruses form a separate genus within the Bunyaviridae family. There are currently >20 recognised sero/genotypes and many others are under investigation. Each hantavirus type appears to be specific to a different rodent host. Virus phylogeny very closely reflects rodent phylogeny. The different hantavirus types are associated with different types of disease both in terms of target organs and disease severity. Two major diseases are recognised: haemorrhagic fever with renal syndrome (HFRS) and HPS. HFRS is primarily a disease of the old world while HPS is only recognised in the Americas. Over the past few decades the understanding and recognition of hantavirus disease throughout the world have greatly expanded. The number of recognised virus types continues to grow, as does the spectrum of hantavirus disease. There is evidence of hantavirus causing human disease in the British Isles, but at present it remains a largely uncharacterised disease.


Mono- and multisite phosphorylation enhances Bcl2's antiapoptotic function and inhibition of cell cycle entry functions.
Bcl2 functions to suppress apoptosis and retard cell cycle entry. Single-site phosphorylation at serine 70 (S70) is required for Bcl2's antiapoptotic function, and multisite phosphorylation at threonine 69 (T69), S70, and S87 has been reported to inactivate Bcl2. To address this apparent conflict and identify the regulatory role for Bcl2 phosphorylation in cell death and cell cycle control, a series of serine/threonine (S/T) --> glutamate/alanine (E/A) mutants including T69E/A, S70E/A, S87E/A, T69E/S70A/S87A (EAA), T69A/S70E/S87A (AEA), T69A/S70A/S87E (AAE), T69E/S70E/S87E (EEE), and T69A/S70A/S87A (AAA) was created to mimic or abrogate, respectively, either single-site or multisite phosphorylation. The survival and cell cycle status of cells expressing the phosphomimetic or nonphosphorylatable Bcl2 mutants were compared. Surprisingly, all of the E but not the A Bcl2 mutants potently enhance cell survival after stress and retard G(1)/S cell cycle transition. The EEE Bcl2 mutant is the most potent, indicating a possible cumulative advantage for multisite phosphorylation of Bcl2 in survival and retardation of G(1)/S transition functions. Because the E-containing Bcl2 mutants, but not the A-containing mutants, can more potently block cytochrome c release from mitochondria during apoptotic stress, even at times when steady-state expression levels are similar for all mutants, we conclude that phosphorylation at one or multiple sites within the flexible loop domain of Bcl2 not only stimulates antiapoptotic activity but also can regulate cell cycle entry.


Empirically derived eating patterns using factor or cluster analysis: a review.
This paper reviews studies performed to date that have employed cluster or factor analysis to empirically derive eating patterns. Since 1980, at least 93 studies were published that used cluster or factor analysis to define dietary exposures, of which 65 were used to test hypotheses or examine associations between patterns and disease outcomes or biomarkers. Studies were conducted in diverse populations across many countries and continents and suggest that patterns are associated with many different biomarkers and disease outcomes, whether measured by cluster or factor analysis. Despite clear differences in approaches and interpretations, there is some evidence that underlying eating patterns are revealed by either method. Although the research considered herein has created a meaningful body of literature, refining both the factor and cluster analysis methods will help to further establish eating patterns as a sound dietary assessment method.


N,N'-Ethylene-bis(iodoacetamide) as a probe for structural and functional characteristics of brine shrimp, squid, and bovine tubulins.
We have developed a simple probe for certain functionally significant features of the tubulin molecule. When bovine brain tubulin is treated with N,N'-ethylene-bis(iodoacetamide) (EBI), two intrachain cross-links, designated beta s and beta *, are formed in beta-tubulin, each one with a unique effect on the electrophoretic mobility of beta on gels containing sodium dodecyl sulfate. Formation of the beta * cross-link, which involves at least one assembly-critical sulfhydryl, is completely inhibited by colchicine and its congeners, while that of beta s is inhibited completely by maytansine and GTP and partly by vinblastine. To see how conserved this complex pattern is in evolution we examined tubulins from the brine shrimp Artemia and the squid Loligo. In both tubulins EBI forms the beta * cross-link in a reaction inhibitable by colchicine, podophyllotoxin, and nocodazole. In each tubulin, EBI appears to form a second intrachain cross-link in a reaction that can be inhibited completely by maytansine and GTP and partly by vinblastine. In Artemia, this cross-link alters the electrophoretic mobility to a slightly smaller extent than is the case for beta s in bovine brain, but in Loligo the alteration is much greater. It seems that the ligand-binding sites, the critical sulfhydryls, and their spatial interrelationships are strongly conserved and that the beta s sulfhydryls or the sequence between them are less strongly conserved in evolution.


Development of targeted hydrophilic interaction liquid chromatography-tandem mass spectrometry method for acyl-Coenzyme A covering short- to long-chain species in a single analytical run.
Acyl-CoAs play a significant role in numerous physiological and metabolic processes making it important to assess their concentration levels for evaluating metabolic health. Considering the important role of acyl-CoAs, it is crucial to develop an analytical method that can analyze these compounds. Due to the structural variations of acyl-CoAs, multiple analytical methods are often required for comprehensive analysis of these compounds, which increases complexity and the analysis time. In this study, we have developed a method using a zwitterionic HILIC column that enables the coverage of free CoA and short- to long-chain acyl-CoA species in one analytical run. Initially, we developed the method using an LC-QTOF instrument for the identification of acyl-CoA species and optimizing their chromatography. Later, a targeted HILIC-MS/MS method was created in scheduled multiple reaction monitoring mode using a QTRAP MS detector. The performance of the method was evaluated based on various parameters such as linearity, precision, recovery and matrix effect. This method was applied to identify the difference in acyl-CoA profiles in HepG2 cells cultured in different conditions. Our findings revealed an increase in levels of acetyl-CoA, medium- and long-chain acyl-CoA while a decrease in the profiles of free CoA in the starved state, indicating a clear alteration in the fatty acid oxidation process.


Symposium on microbiology update: old friends and new enemies. Clostridium perfringens.
In the United States and Canada, Clostridium perfringens remains a leading cause of bacterial food poisoning in humans. It has been primarily associated with meat and poultry products prepared in food service establishments. Fecal spore levels of 10(6) or more per g are considered indicative of a food poisoning outbreak. However, elevated spore levels of this organism are frequently seen in healthy elderly individuals, an observation that complicates investigations of suspected outbreaks. Recent studies with this population indicate that fecal enterotoxin levels are a valuable and effective assay for confirming outbreaks due to this organism. With regard to the toxin itself, a membrane protein of 50 000-70,000 molecular weight has been isolated as a possible enterotoxin-receptor site. It is the subsequent action of the toxin on membrane structure that results in the loss of ions and fluid associated with illness. In addition, the enterotoxin gene has been cloned in E. coli and sequenced. Using toxin-specific DNA probes, only 6% of non-symptomatic farm animals were found to possess the enterotoxin gene, disproving the hypothesis that all strains of this organism can produce the toxin.


Hypolipidemic and hepatoprotective activities of rosemary and thyme in gentamicin-treated rats.
Rosemary ( Rosmarinus officinalis; RM) and thyme ( Thymus vulgaris; TV) are used as remedies. We designed this work to investigate the preventive effect of aqueous extracts of RM or TV on the gentamicin (GM)-induced hepatotoxicity and abnormalities of lipid profile in rats. Both plant extracts exhibited an in vitro antioxidant activity as determined by the 1,1-diphenyl-2-picrylhydrazyl assay. Radical scavenging activity for TV extract was 48.7% and for RM extract was 25.6%. Polyphenolic determination by high-performance liquid chromatography for both extracts revealed that catechin, coumarin, cinnamic acid and rutin were detected in both extracts. RM extract had higher values than TV extract in all except rutin. Ferulic acid and quercetin were also detected in TV extract and sinapic acid and oleuropein were detected in RM extract. In rats given GM intraperitoneally for 10 days and coadministered either RM extract or TV extract orally, both aqueous extracts demonstrated similar hepatoprotective effects manifested by approximate normalization of plasma liver enzymes (AST and ALT), bilirubin level and total protein concentration compared with the group given GM only. Abnormal lipid parameters and raised hydrogen peroxide levels were ameliorated by both extracts. Pancreatic lipase activity was markedly reduced by RM extract. Also, the atherogenic index value was significantly reduced by both extracts as compared to that of GM group. DNA fragmentation analysis confirmed tissue damage by GM and its amelioration by the extracts. These findings suggest that RM and TV extracts could be helpful in ameliorating some aspects of gentamicin toxicity.


Attitudes of Pediatricians Regarding Prevention and Treatment of Vitamin D Deficiency.
To determine the adherence of pediatricians to the nationwide 'Vitamin D Prophylaxis Program' and to evaluate their attitudes about vitamin D intake. The study was conducted using the Turkish National Pediatrics Association network. The pediatricians were asked to respond to an online questionnaire that included five questions on 'What dose of vitamin D they recommend for supplementation?', 'At what age they start vitamin D supplementation?', 'Supplementation method', 'Clichés and truths about vitamin D', and 'High-dose vitamin D therapy indications'. Responses of 167 pediatricians were evaluated in this study. 75.5% of pediatricians indicated that they recommended vitamin D supplementation in a daily dose of 400 IU. 47.1% started vitamin D supplementation by the end of the 2nd week. 7.83% of pediatricians suggested doubling the daily dose of vitamin D supplementation in infants with delayed tooth eruption, 19.9% suggested immediate cessation of vitamin D supplementation in infants with small anterior fontanels. This study showed that the majority of the pediatricians still prescribe vitamin D prophylaxis late, recommend high doses of vitamin D in cases of delayed tooth eruption, and think that low serum 25-hydroxy vitamin D level regardless of alkaline or phosphatase parathyroid hormone measurement is an indication for high-dose vitamin D (stoss) therapy. These results suggest a need for new training programs focusing on vitamin D supplementation.


The thiazole derivative CPTH6 impairs autophagy.
We have previously demonstrated that the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) induces apoptosis and cell cycle arrest in human leukemia cells. The aim of this study was to evaluate whether CPTH6 is able to affect autophagy. By using several human tumor cell lines with different origins we demonstrated that CPTH6 treatment induced, in a dose-dependent manner, a significant increase in autophagic features, as imaged by electron microscopy, immunoblotting analysis of membrane-bound form of microtubule-associated protein 1 light chain 3 (LC3B-II) levels and by appearance of typical LC3B-II-associated autophagosomal puncta. To gain insights into the molecular mechanisms of elevated markers of autophagy induced by CPTH6 treatment, we silenced the expression of several proteins acting at different steps of autophagy. We found that the effect of CPTH6 on autophagy developed through a noncanonical mechanism that did not require beclin-1-dependent nucleation, but involved Atg-7-mediated elongation of autophagosomal membranes. Strikingly, a combined treatment of CPTH6 with late-stage autophagy inhibitors, such as chloroquine and bafilomycin A1, demonstrates that under basal condition CPTH6 reduces autophagosome turnover through an impairment of their degradation pathway, rather than enhancing autophagosome formation, as confirmed by immunofluorescence experiments. According to these results, CPTH6-induced enhancement of autophagy substrate p62 and NBR1 protein levels confirms a blockage of autophagic cargo degradation. In addition, CPTH6 inhibited autophagosome maturation and compounds having high structural similarities with CPTH6 produced similar effects on the autophagic pathway. Finally, the evidence that CPTH6 treatment decreased α-tubulin acetylation and failed to increase autophagic markers in cells in which acetyltransferase ATAT1 expression was silenced indicates a possible role of α-tubulin acetylation in CPTH6-induced alteration in autophagy. Overall, CPTH6 could be a valuable agent for the treatment of cancer and should be further studied as a possible antineoplastic agent.


Estradiol‑enhanced osteogenesis of rat bone marrow stromal cells is associated with the JNK pathway.
Bone marrow stromal cells (BMSCs) can differentiate into osteoblasts. The present study investigated the osteogenic effects of estradiol, as well as the role of the c‑Jun N‑terminal kinase (JNK) signaling pathway in promoting estradiol‑enhanced osteogenesis of rat (r)BMSCs. rBMSCs were treated for 7 days with or without estradiol and further treated with or without the JNK‑specific inhibitor SP600125. The role of estrogen during rBMSC osteogenesis was evaluated by alkaline phosphatase activity and mineralized nodule formation using the Gomori method and Alizarin red S staining, respectively. Subsequently, the mRNA expression levels of transforming growth factor-β1 (TGF‑β1) and core‑binding factor α1 (Cbfα1) were evaluated by reverse transcription‑quantitative polymerase chain reaction, and TGF‑β1, Cbfα1 and phosphorylated (p)‑JNK protein expression was detected by western blotting. All groups treated with SP600125 expressed low levels of TGF‑β1 and Cbfα1 mRNA and protein, and low p‑JNK protein expression. Compared with the control cells, rBMSCs cultured with estradiol exhibited a significant upregulation in the expression levels of osteogenic genes and proteins. The present study demonstrated that estradiol enhanced osteogenic differentiation of rBMSCs and that the JNK signaling pathway was involved in this process, providing insights into the molecular mechanisms involved in rBMSC osteogenesis upon estradiol stimulation.


Identification and Characterization of Spontaneous Auxotrophic Mutants in Fusarium langsethiae.
Analysis of 49 strains of Fusarium langsethiae originating from northern Europe (Russia, Finland, Sweden, UK, Norway, and Latvia) revealed the presence of spontaneous auxotrophic mutants that reflect natural intraspecific diversity. Our investigations detected that 49.0% of F. langsethiae strains were auxotrophic mutants for biotin, and 8.2% of the strains required thiamine as a growth factor. They failed to grow on vitamin-free media. For both prototrophic and auxotrophic strains, no growth defect was observed in rich organic media. Without essential vitamins, a significant reduction in the growth of the auxotrophic strains results in a decrease of the formation of T-2 toxin and diacetoxyscirpenol. In addition, all analysed F. langsethiae strains were distinguished into two subgroups based on PCR product sizes. According to our results, 26 and 23 strains of F. langsethiae belong to subgroups I and II respectively. We determined that the deletion in the intergenic spacer (IGS) region of the rDNA of F. langsethiae belonging to subgroup II is linked with temperature sensitivity and causes a decrease in strain growth at 30 °C. Four thiamine auxotrophic strains were found in subgroup I, while 21 biotin auxotrophic strains were detected in subgroups II. To the best of our knowledge, the spontaneous mutations in F. langsethiae observed in the present work have not been previously reported.


Undifferentiated carcinoma with lymphoid stroma of the parotid gland.
Six cases of undifferentiated carcinoma of the parotid gland with heavy lymphocytic infiltration have been treated at Montreal General Hospital over the past 23 years. A thorough review of the literature revealed another 31 similar cases which are discussed. For unknown reasons, these malignant tumors seem to be more common in North American Inuit. Their relatively better prognosis may be attributed to the protective function of the heavy lymphocytic infiltration. Surgery has been the treatment of choice with postoperative radiotherapy in indicated cases. Longer follow-up is necessary to assess the role of lymphocytic infiltration in improving survival.


A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers.
Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines. Here, we studied the therapeutic effect of b-AP15 in PCa, and our results indicate that (i) b-AP15 decreases viability, proliferation and triggers cytotoxicity to both androgen receptor-dependent and -independent PCa cells in vitro and in vivo, associated with caspase activation, inhibition of mitochondria function, increased reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress; (ii) pan-caspase inhibitor z-VAD-FMK and ROS scavenger N-acetyl-L-cysteine (NAC) efficiently block apoptosis but not proteasome inhibition induced by exposure of b-AP15; (iii) treatment with b-AP15 in androgen-dependent prostate cancer (ADPC) cells down-regulates the expression of androgen receptor (AR), which is degraded via the ubiquitin proteasome system. Hence, the potent anti-tumor effect of b-AP15 on both androgen receptor-dependent and -independent PCa cells identifies a new promising therapeutic strategy for prostate cancer.


[Spatial and temporary changes in sensitivity of murine proliferative system and energy exchange to typhoid fever infection].
The authors studied the spatial and temporary organization of the proliferative system and energy exchange in the small intestinal epithelium, as well as spatial and temporary changes in the sensitivity of these systems in mice to typhoid fever infection (cultured Salmonella typhi, 4446) at day and night. The small intestinal epithelial systems were found to show a spatial and time organization and a close correlation between their temporary and spatial changes after infection. The temporary organization of the proliferative system in the esophageal epithelium is more sensitive to infection in the day-time and that of the small intestinal epithelial proliferative system is more marked at night. Thus, these changes are tissue-specific. Typhoid fever infection causes a negative effect on the proliferative system of the small intestine at night and on its energy exchange in the day-time, which shows the system-specific response of the temporary organization of a biological process within the same organ. The changes in the spatial proliferative and energy exchange parameters in the small intestinal epithelium, which have been caused by the infection of animals, depend on the time of a day.


Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor.
Glomerular influx of monocytes/macrophages (M/M) occurs in many immune- and non-immune-mediated renal diseases. The mechanisms targeting M/M into the glomerulus are incompletely understood, but may involve stimulated expression of chemokines. We investigated whether angiotensin II (ANG II) induces the chemokine RANTES in cultured glomerular endothelial cells of the rat and in vivo. ANG II stimulated mRNA and protein expression of RANTES in cultured glomerular endothelial cells. The ANG II-induced RANTES protein was chemotactic for human monocytes. Surprisingly, the ANG II-stimulated RANTES expression was transduced by AT2 receptors because the AT2 receptor antagonists PD 123177 and CGP-42112A, but not an AT1 receptor blocker, abolished the induced RANTES synthesis. Intraperitoneal infusion of ANG II (500 ng/h) into naive rats for 4 d significantly stimulated glomerular RANTES mRNA and protein expression compared with solvent-infused controls. Immunohistochemistry revealed induction of RANTES protein mainly in glomerular endothelial cells and small capillaries. Moreover, ANG II- infused animals exhibited an increase in glomerular ED-1- positive cells compared with controls. Oral treatment with PD 123177 (50 mg/liter drinking water) attenuated the glomerular M/M influx without normalizing the slightly elevated systolic blood pressure caused by ANG II infusion, suggesting that the effects on blood pressure and RANTES induction can be separated. We conclude that the vasoactive peptide ANG II may play an important role in glomerular chemotaxis of M/M through local induction of the chemokine RANTES. The observation that the ANG II- mediated induction of RANTES is transduced by AT2 receptors may influence the decision as to which substances might be used for the therapeutic interference with the activity of the renin-angiotensin system.


Predictive values of serum and bulk milk sampling for the presence of persistently infected BVDV carriers in dairy herds.
The aim of this study was to examine whether it is possible to predict the presence of persistently infected (PI) animals with bovine viral diarrhoea virus on dairy farms in The Netherlands, based on a few blood samples of the herd, possibly in combination with a bulk milk test for antibodies. In 25 herds with, and 24 herds without, PI animal(s) the probabilities of obtaining at least x antibody positive animals out of a sample of n animals were calculated, with n varying from 3 to 7 and values for x that were considered were n, n - 1 to n - x. This probability, among animals 9-24 months old, ranged from 0.70 to 0.96 for herds with PI animals and from 0.13 to 0.37 for herds without. Using the result of bulk milk testing in addition did not add to the prediction. It was concluded that, due to the high percentage and large variation of antibody positive animals in herds without PI animals, it is not possible to predict the presence of PI animal(s) in dairy herds in The Netherlands using these methods.


Microfluidics of imbibition in random porous media.
A free-energy lattice Boltzmann approach has been used to perform simulations of liquid penetration into random porous media. We focus our study on the effects of microstructures, particularly microtopography, on liquid penetration driven by capillary force and external pressure. For this purpose we set up a model structure that consists of a network of interconnected capillaries with varying pore geometries. The results showed that the discontinuities in the solid-surface curvature, as are present as corners on the capillary surfaces, have strong influences on liquid penetration through their pinning effects and interactions with local geometry.


FDA critical path initiatives: opportunities for generic drug development.
FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.


Consideration of methodological issues when using photo-elicitation in qualitative research.
The use of photo-elicitation interviews (PEIs) has increased in popularity across a range of disciplines including healthcare. Although qualitative researchers have embraced PEIs as a creative way to explore people's experiences of their lives and environments, the methodological and practical aspects of using photographs have received little attention in the literature. To discuss the use of PEI techniques, including sourcing and using photographs. The authors discuss definitions of photo-elicitation, and explore the value of and difference between using photographs taken by the researcher and those taken by participants. They consider methodological issues in the context of a small-scale focus group study that used PEIs to explore young women's conceptualisations of teenage and older motherhood. Using photographs in research is far more complex than providing participants with cameras or presenting them with photographs. Researchers must be aware of the potential bias in the choice, selection and sequencing of photographs, as well as the methodological considerations associated with PEIs. This article highlights the value of using photographs in qualitative research and presents some of the methodological issues that nurse researchers need to consider when designing and conducting research using photographs.


Effects of depsidones from Hypogymnia physodes on HeLa cell viability and growth.
The anti-proliferative activitiy of Hypogymnia physodes methanol extracts (ME) and its main constituents, physodalic acid (P1), physodic acid (P2), and 3-hydroxy physodic acid (P3), was tested on human cancer HeLa cell lines. Three lichen depsidones, P1, P2 and P3, were isolated from H. physodes ME using column chromatography and their structures were determined by UV, ESI TOF MS, 1H and 13C NMR. The content of P1, P2 and P3 in ME was determined using reversed-phase highperformance liquid chromatography with photodiode array detection. P1-3 represented even 70 % of the studied extract. The HeLa cells were incubated during 24 and 72 h in the presence of ME and depsidones P1, P2 and P3, at concentrations of 10-1000 μg/ml. Compounds P2 and P3 showed higher activity than compound P1. Half maximal inhibitory concentrations (IC50, μg/ml) of P1, P2, P3 and ME for 24-h incubation were 964, 171, 97 and 254 μg/ml, respectively, while for 72-h incubation they were 283, 66, 63 and 68 μg/ml. As far as we know, this is the first report on the effect of H. physodes ME and their depsidones on HeLa cells.


Reliability and validity of Chinese version of brace questionnaire for adolescent idiopathic scoliosis: A cross-sectional study.
There is an increasing concern about the impact of bracing on the quality of life (QoL) of patients with adolescent idiopathic scoliosis (AIS). However, up to now, few multidimensional questionnaires on this impact are available in China. This study aimed to evaluate the reliability and validity of the Chinese version of Brace Questionnaire (C-BrQ).The BrQ was translated from Greek into Chinese with proper cross-cultural adaptation.An observational, cross-sectional study in Chinese patients with AIS was conducted to measure the temporal stability of C-BrQ using the intraclass correlation coefficient (ICC). The effects of ceiling and floor were evaluated and the reliability was verified by examining the internal consistency. The C-BrQ domains were compared with the domains in Chinese version of Scoliosis Research Society-22 Outcomes Questionnaire (C-SRS-22) using Pearson correlation coefficient to assess the concurrent validity.A total of 208 patients were included in the study. The results of test-retest reliability for each dimension of C-BrQ were desirable. The floor or ceiling effects were not demonstrated in the C-BrQ and C-SRS-22. Satisfactory internal consistency was found in all the C-BrQ domains. Most C-BrQ and C-SRS-22 domains showed satisfactory correlation coefficients, except when vitality and school activity in C-BrQ were compared with self-image, mental health, and management satisfaction in C-SRS -22, respectively.C-BrQ is reliable in evaluating the QoL of AIS patients receiving brace treatment.


NMR structures of thioredoxin m from the green alga Chlamydomonas reinhardtii.
Chloroplast thioredoxin m from the green alga Chlamydomomas reinhardtii is very efficiently reduced in vitro and in vivo in the presence of photoreduced ferredoxin and a ferredoxin dependent ferredoxin-thioredoxin reductase. Once reduced, thioredoxin m has the capability to quickly activate the NADP malate dehydrogenase (EC 126.96.36.199) a regulatory enzyme involved in an energy-dependent assimilation of carbon dioxide in C4 plants. This activation is the result of the reduction of two disulfide bridges by thioredoxin m, that are located at the N- and C-terminii of the NADP malate dehydrogenase. The molecular structure of thioredoxin m was solved using NMR and compared to other known thioredoxins. Thioredoxin m belongs to the prokaryotic type of thioredoxin, which is divergent from the eukaryotic-type thioredoxins also represented in plants by the h (cytosolic) and f (chloroplastic) types of thioredoxins. The dynamics of the molecule have been assessed using (15)N relaxation data and are found to correlate well with regions of disorder found in the calculated NMR ensemble. The results obtained provide a novel basis to interpret the thioredoxin dependence of the activation of chloroplast NADP-malate dehydrogenase. The specific catalytic mechanism that takes place in the active site of thioredoxins is also discussed on the basis of the recent new understanding and especially in the light of the dual general acid-base catalysis exerted on the two cysteines of the redox active site. It is proposed that the two cysteines of the redox active site may insulate each other from solvent attack by specific packing of invariable hydrophobic amino acids.