Substance use prevention and treatment outcomes for emerging adults in non-college settings: A meta-analysis.
Emerging adults have the highest prevalence rate of alcohol and drug use and represent a large proportion of treatment admissions in the United States. Those who do not attend college experience higher rates of use and may not have similar advantages as those attending college. A systematic review included studies investigating prevention and treatment outcomes among emerging adults in non-college settings. We included studies reporting an average age between 18 and 25 conducted outside of college settings. We extracted data for experimental effects (experimental group compared to control), and contrasted treatments with active and no intervention controls. We also examined several moderators. Fifty studies were meta-analyzed, including 32 prevention and 18 treatment studies. Overall, our experimental weighted mean effect size was d = .17 for both prevention and treatment studies. Comparisons across treatment types typically yielded nonsignificant results. Across prevention and treatment studies, smaller effects existed for studies delivering personalized feedback interventions. For treatment studies only, the percent of students included in the sample was a significant moderator. Overall effects were similar to current meta-analyses on college drinking. However, personalized feedback may be a less effective prevention strategy in non-college settings, and the field should prioritize increasing the effectiveness of treatments targeting non-college students. (PsycINFO Database Record


Development and assessment of the Alberta Context Tool.
The context of healthcare organizations such as hospitals is increasingly accepted as having the potential to influence the use of new knowledge. However, the mechanisms by which the organizational context influences evidence-based practices are not well understood. Current measures of organizational context lack a theory-informed approach, lack construct clarity and generally have modest psychometric properties. This paper presents the development and initial psychometric validation of the Alberta Context Tool (ACT), an eight dimension measure of organizational context for healthcare settings. Three principles guided the development of the ACT: substantive theory, brevity, and modifiability. The Promoting Action on Research Implementation in Health Services (PARiHS) framework and related literature were used to guide selection of items in the ACT. The ACT was required to be brief enough to be tolerated in busy and resource stretched work settings and to assess concepts of organizational context that were potentially modifiable. The English version of the ACT was completed by 764 nurses (752 valid responses) working in seven Canadian pediatric care hospitals as part of its initial validation. Cronbach's alpha, exploratory factor analysis, analysis of variance, and tests of association were used to assess instrument reliability and validity. Factor analysis indicated a 13-factor solution (accounting for 59.26% of the variance in 'organizational context'). The composition of the factors was similar to those originally conceptualized. Cronbach's alpha for the 13 factors ranged from .54 to .91 with 4 factors performing below the commonly accepted alpha cut off of .70. Bivariate associations between instrumental research utilization levels (which the ACT was developed to predict) and the ACT's 13 factors were statistically significant at the 5% level for 12 of the 13 factors. Each factor also showed a trend of increasing mean score ranging from the lowest level to the highest level of instrumental research use, indicating construct validity. To date, no completely satisfactory measures of organizational context are available for use in healthcare. The ACT assesses several core domains to provide a comprehensive account of organizational context in healthcare settings. The tool's strengths are its brevity (allowing it to be completed in busy healthcare settings) and its focus on dimensions of organizational context that are modifiable. Refinements of the instrument for acute, long term care, and home care settings are ongoing.


Interobserver and intraobserver variability in the calculation of the lipid-laden macrophage index: implications for its use in the evaluation of aspiration in children.
The lipid-laden macrophage index (LLMI) is a semiquantitative test used to evaluate aspiration in children. We assessed the reliability and reproducibility of LLMI by calculating interobserver and intraobserver variability among pathologists, with and without expertise in cytopathology. Forty-nine bronchoalveolar washes/lavages were blindly reviewed by four reviewers and assigned an LLMI. Three pathologists (two cytopathologists, one pathology fellow) reviewed slides twice and one cytotechnologist reviewed them once. Intraclass correlation coefficient (ICC) with 95% confidence interval (C.I.) was used to measure overall intraobserver and interobserver agreement. Interobserver agreement was also calculated separately for each pair of reviewers. ICC values did not indicate an acceptable level of interobserver agreement among pathologists, with (ICC = 0.67, 95% C.I.: 0.56-0.77) and without (ICC = 0.77, 95% C.I.: 0.61-0.84) the cytotechnologist included in the analysis. An ICC of 0.84 (95% C.I.: 0.78-0.89) indicated an acceptable level of intraobserver agreement among pathologists. When calculated separately for each pair of reviewers, all but two ICC values for interobserver agreement were less than 0.75 (the minimally acceptable value for a reliable clinical measurement), and the lower confidence limit of each of the 95% C.I. was far below the 0.75 cutoff. Using Lin's coefficient, intraobserver variability was only acceptable for two pathologists. Our study highlights the lack of precision and subjectivity of the LLMI, as well as the significant inter and intraobserver bias that may occur among experienced and inexperienced pathologists, and cytotechnologists. Clinicians and cytopathologists alike should be mindful of this potential pitfall and interpret LLMI scores with caution.


Mean, variance, and autocorrelation of subthreshold potential fluctuations driven by filtered conductance shot noise.
We study the subthreshold voltage fluctuations of a conductance-based passive point neuron stimulated by filtered Poissonian shot noise. We give exact analytical expressions in terms of quadratures for the first two time-dependent moments and the autocorrelation function of the membrane voltage. We also derive simplified expressions for the moments in terms of elementary functions that hold true in the limit case of short filter time, small spike amplitude, and a single synaptic reversal potential. By means of these expressions, we show that for an ensemble of equilibrated conductances but sharp initial voltage (corresponding to a short voltage clamp at the initial time), the mean and the standard deviation can display nonmonotonic time courses. In particular, transient changes in the standard deviation disagree strongly with the predictions of the commonly used effective time constant approximation over a large parameter range. We also study the dependence of the correlation time of the voltage on the synaptic spike amplitude and the synaptic input rate. All results are confirmed by extensive stochastic simulations.


Current concepts in urinary tract infections.
Urinary tract infections (UTIs) are common infectious diseases that can be associated with substantial morbidity and significant expenditures. This review highlights the current concepts and recent advances in our understanding and management of this condition. Specific topics include pathogenesis, host factors, antimicrobial resistance, recurrent UTIs in women, diagnosis, treatment of uncomplicated and complicated UTIs, prophylaxis, catheter associated bacteriuria, pregnancy, diabetes, UTIs in men, prostatitis, and the chronic pelvic pain syndrome. UTIs can be viewed as an interaction between specific bacterial virulence factors and the patient. A new model explaining the pathogenesis of recurrent UTIs has been presented. There is a need to reconsider traditional treatment recommendations in the face of local resistance patterns, as well as the need to make better use of drugs that are currently available. Prospects for prevention of recurrent UTI include natural compounds, bacterial interference and immunization. With regard to UTI risk in women, patients can be classified based on age, and functional and hormonal status. Appropriate treatment approaches must be based on this classification. In contrast to uncomplicated UTIs, management of most complicated infections depends on clinical experience and resources at individual institutions rather than on evidence based guidelines. Asymptomatic bacteriuria generally should not be treated except in high-risk catheterized patients and in pregnancy. UTIs in men generally require formal urologic evaluation. Our understanding of the etiologies, diagnostic strategies, and treatment options for prostatitis and the chronic pelvic pain syndrome in men continues to evolve.


Hematopoietic stem cell transplantation in Oman.
Hematopoietic SCT (HSCT) is an integral part of the management of patients with hematologic disorders. The Sultanate of Oman, with a population of 2.3 million, has an HSCT program based in the Sultan Qaboos University (SQU) hospital. Initiated in 1995, this two-bed unit continues to be the only program in the country. Between June 1995 and August 2006, a total of 128 patients underwent HSCT in this center, averaging about 10-12 transplants per year. The median age of these patients was 11 years (2 months to 45 years). Hematologic malignancies (49%) and inherited disorders (42%) constituted the major transplant indications, whereas BM failure accounted for the remaining. The majority of transplants carried out so far have been HLA-matched sibling-donor allogeneic HSCTs. Among the inherited disorders, homozygous beta-thalassemia and primary immunodeficiency are important transplant indications in this center. The approximate cost of an uncomplicated transplant in this center is US$50,000. The success of this program has now led to the initiation of a new and larger HSCT complex to provide the opportunity for more patients to benefit from this treatment modality within the country.


Development of small molecule inhibitors and probes of human SUMO deconjugating proteases.
Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation.


Investigation of Burkholderia cepacia nosocomial outbreak with high fatality in patients suffering from diseases other than cystic fibrosis.
Over a 1-y period, 26 inpatients at the Jordan University Hospital in Amman were detected with bacteraemia (23 cases) or respiratory tract colonized with B. cepacia (3 cases). A combination of genetic identification and molecular typing has proved that all cases were caused by a single epidemic strain of B. cepacia genomovar IIIa. Nosocomial infections could be documented in 21/26 (81%) patients, mostly with severe underlying or malignant diseases other than cystic fibrosis, but the source of infection was undetected. The overall mortality related to infection with B. cepacia was 42%. All B. cepacia isolates were resistant to ampicillin, amikacin, carbenicillin and gentamicin; and mostly susceptible to piperacillin, chloramphenicol, cotri-moxazole, tetracycline, ceftazidime, and tazocin (62-88%). This study demonstrates the nosocomial and high fatality of B. cepacia genomovar IIIa in Jordanian patients suffering from diseases other than cystic fibrosis.


Mixed integer linear programming for maximum-parsimony phylogeny inference.
Reconstruction of phylogenetic trees is a fundamental problem in computational biology. While excellent heuristic methods are available for many variants of this problem, new advances in phylogeny inference will be required if we are to be able to continue to make effective use of the rapidly growing stores of variation data now being gathered. In this paper, we present two integer linear programming (ILP) formulations to find the most parsimonious phylogenetic tree from a set of binary variation data. One method uses a flow-based formulation that can produce exponential numbers of variables and constraints in the worst case. The method has, however, proven extremely efficient in practice on datasets that are well beyond the reach of the available provably efficient methods, solving several large mtDNA and Y-chromosome instances within a few seconds and giving provably optimal results in times competitive with fast heuristics than cannot guarantee optimality. An alternative formulation establishes that the problem can be solved with a polynomial-sized ILP. We further present a web server developed based on the exponential-sized ILP that performs fast maximum parsimony inferences and serves as a front end to a database of precomputed phylogenies spanning the human genome.


Defective natural killer cell anti-viral capacity in paediatric HBV infection.
Natural killer (NK) cells exhibit dysregulated effector function in adult chronic hepatitis B virus (HBV) infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK cell frequency, phenotype and function in HBV-infected children relative to uninfected children. We observed a selective defect in NK cell interferon (IFN)-γ production, with conserved cytolytic function, mirroring the functional dichotomy observed in adult infection. Reduced expression of NKp30 on NK cells suggests a role of impaired NK-dendritic cell (DC) cellular interactions as a potential mechanism leading to reduced IFN-γ production. The finding that NK cells are already defective in paediatric CHB, albeit less extensively than in adult CHB, has potential implications for the timing of anti-viral therapy aiming to restore immune control.


Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis.
Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis.


The influence of age on lip-line cant in adults: a cross-sectional study.
The aims of this study were to assess the direction and degree of lip-line cant in Korean adult orthodontic patients and to identify the effects of sex and age on changes in the cant severity. In this cross-sectional retrospective study, lip-line cant was measured in the frontal photographs of 585 Korean patients (92 men and 493 women) aged 18-48 years. The outcome variables (direction and degree of lip-line cant) were assessed in terms of predictor variables (sex, age, sagittal skeletal relationship, and menton deviation angle). The direction of lip-line cant did not differ according to sex, age, or skeletal classification. Patients had 1.6° of lip-line cant on average before orthodontic treatment. Middle-aged adults displayed a significant trend toward a lower degree of lip-line cant compared to younger adults (p < 0.01). Multiple linear regression analysis showed that the degree of lip-line cant was weakly negatively correlated with age (p < 0.001). While the direction of lip-line cant did not differ according to the parameters explored here, the degree of cant was correlated with age in adults, independent of menton deviation. Specifically, middle-aged adults tended to display significantly lower degrees of lip-line cant than did younger adults.


Mechanism of ascorbic acid-induced reversion against malignant phenotype in human gastric cancer cells.
To find out the mechanisms of redifferentiation and reversion of malignant human gastric cancer cells induced by ascorbic acid. Human gastric cancer cells grown in the laboratory were used. The Trypan blue dye exclusion method was used to determine the cell doubling time. The electrophoresis rate and colonogenic potential were the indices used to measure the rate of redifferentiation. The content of malondialdehyde (MDA) was measured using the thiobarbituric acid (TBA) method. The activities of superoxide dismutase (SOD), catalase (CAT) and the content of H202 were evaluated by spectrophotography. Six mmol/L ascorbic acid was used as a positive control. Human gastric cancer cells were treated with 75 microm hydrogen peroxide, which alleviated many of the malignant characteristics. For example, the cell surface charge obviously decreased and the electrophoresis rate dropped from 2.21 to 1.10 microm x s(-1) x V(-1) x cm(-1). The colonogenic potential, a measure of cell differentiation, decreased 90.2%. After treatment with ascorbic acid, there was a concentration- and time-dependent increase in hydrogen peroxide (H202) and the activity of superoxide dismutase (SOD). However, the activity of catalase (CAT) resulted in a concentration- and time-dependent decrease. SOD and 3-amino-1,2,4-triazole (AT) exhibited some effects, but there were statistically significant differences between the SOD and AT group and the H202 group. Ascorbic acid induces growth inhibition and redifferentiation of human gastric cancer cells through the production of hydrogen peroxide.


Exposure to combined oral contraceptives and risk of venous thromboembolism: a protocol for nested case-control studies using the QResearch and the CPRD databases.
Many studies have found an increased risk of venous thromboembolism (VTE) associated with the use of combined hormonal contraceptives, but various methodologies have been used in the study design relating to definition of VTE event and the selection of appropriate cases for analysis. This study will focus on common oral hormonal contraceptives, including compositions with cyproterone because of their contraceptive effect and will perform a number of sensitivity analyses to compare findings with previous studies. 2 nested case-control studies will be based on the general population using records from UK general practices within the QResearch and Clinical Practice Research Datalink databases. Cases will be female patients aged 15-49 with primary VTE diagnosed between 2001 and 2013. Each case will be matched by age, year of birth and practice to five female controls, who are alive and registered with the practice at the time of diagnosis of the case (index date). Exposure to different hormonal contraceptives will be defined as at least one prescription for that contraceptive in the year before the index date. The effects of duration and the length of any gap since last use will also be investigated. Conditional logistic regression will be applied to calculate ORs adjusted for smoking, ethnicity, comorbidities and use of other medications. Possible indications for prescribing hormonal contraceptives, such as menstrual disorders, acne or hirsutism will be included in the analyses as confounding factors. A number of sensitivity analyses will be carried out. The initial protocol has been reviewed and approved by ISAC (Independent Scientific Advisory Committee) for Medicine and Healthcare Products Regulatory Agency Database Research. The project has also been reviewed by QResearch and meets the requirements of the Trent Research Ethics Committee. The results will be published in a peer-reviewed journal.


IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component.
The bronchial epithelium is a source of both alpha and beta chemokines and, uniquely, of secretory component (SC), the extracellular ligand-binding domain of the polymeric IgA receptor. Ig superfamily relatives of SC, such as IgG and alpha(2)-macroglobulin, bind IL-8. Therefore, we tested the hypothesis that SC binds IL-8, modifying its activity as a neutrophil chemoattractant. Primary bronchial epithelial cells were cultured under conditions to optimize SC synthesis. The chemokines IL-8, epithelial neutrophil-activating peptide-78, growth-related oncogene alpha, and RANTES were released constitutively by epithelial cells from both normal and asthmatic donors and detected in high m.w. complexes with SC. There were no qualitative differences in the production of SC-chemokine complexes by epithelial cells from normal or asthmatic donors, and in all cases this was the only form of chemokine detected. SC contains 15% N-linked carbohydrate, and complete deglycosylation with peptide N-glycosidase F abolished IL-8 binding. In micro-Boyden chamber assays, no IL-8-dependent neutrophil chemotactic responses to epithelial culture supernatants could be demonstrated. SC dose-dependently (IC(50) approximately 0.3 nM) inhibited the neutrophil chemotactic response to rIL-8 (10 nM) in micro-Boyden chamber assays and also inhibited IL-8-mediated neutrophil transendothelial migration. SC inhibited the binding of IL-8 to nonspecific binding sites on polycarbonate filters and endothelial cell monolayers, and therefore the formation of haptotactic gradients, without effects on IL-8 binding to specific receptors on neutrophils. The data indicate that in the airways IL-8 may be solubilized and inactivated by binding to SC.


The role of flow cytometry in celiac disease screening using human leukocyte antigen in adult patients with type 1 diabetes mellitus.
Patients with type 1 diabetes mellitus (DM1) have an increased risk of celiac disease (CD). Since CD can be seronegative, more sensible tests for detection are needed. In seronegative patients, CD diagnosis may be difficult because of a lack of specificity. Flow cytometry analysis of lymphocyte populations can be useful in this situation. We aimed to study the prevalence of CD in adult DM1 using human leukocyte antigen (HLA) compatibility-based screening. A secondary goal was to study the role of flow cytometry as a complementary tool in these patients. We selected 200 patients with DM1, of whom 190 (95%) had HLA DQ2, DQ8 or both. Of these, 136 agreed to participate and provided epidemiological data. All patients underwent blood tests and gastroscopy. Sixteen patients had a histology consistent with CD. After ruling out other diagnoses, 6 patients were diagnosed with CD, 2 of whom had negative antibodies. All were DQ2.5 homozygous, with a CD prevalence of 9.8% in this group. In the flow cytometry analysis of duodenal biopsy samples, when we compared all non-CD with CD patients, we found that the γ/δ intraepithelial lymphocyte (IEL) percentage was significantly higher and the CD3 negative IEL percentage significantly lower in the CD group. We found similar results when we compared only those with histological lesions. Screening of CD in patients with DM1 by HLA detects only 1% of seronegative patients with CD. DQ2.5 homozygous patients are at most risk of developing CD. The study of lymphocyte populations in the duodenal biopsy by flow cytometry discriminates patients with CD from those without CD with high sensitivity and specificity.


Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir.
Ritonavir is an antiretroviral drug characterized by low solubility and high permeability which corresponds to BCS class II drug. The purpose of the study was to develop solid dispersion by different methods and investigate them for in vitro and in vivo performance for enhancing dissolution and bioavailability, respectively. Since the drug possesses food-related absorption, the effect of biorelevant media (FaSSIF and FeSSIF state) on dissolution behavior was also studied. The solid dispersion was prepared using Gelucire as carrier in 1:4 ratio by different methods and were characterized for differential scanning calorimetry (DSC), X-ray diffractometry, scanning electron microscopy, and FT-IR. Oral bioavailability of 10 mg of ritonavir in solid dispersion prepared by solvent evaporation (SE1) and melt method (MM1) was compared with pure drug after oral administration of solid dispersion and pure drug to Albino Wistar rats of either sex. The results suggested formation of eutectic solid dispersion. In vitro dissolution studies was performed in 0.1 N HCl and biorelevant media showed enhanced dissolution rate as compared to pure drug in both FeSSIF media and 0.1 N HCl. The apparent rate of absorption of ritonavir from SE1 (C(max) 20221.37 ng/ml, t(max) 0.5 h) was higher than that of MM1 (C(max) 2,462.2, t(max) 1 h) and pure drug (C(max) 1,354.8 ng/ml, t(max) 0.5 h). On the basis of the result obtained, it was concluded that solid dispersion is a good approach to enhance solubility and bioavailability of poorly water-soluble ritonavir.


Bacterial type two secretion system secreted proteins: double-edged swords for plant pathogens.
The type two secretion system (T2S) is important for virulence of a number of gram-negative bacterial plant pathogens. Most of the T2S-secreted proteins that have been characterized to date are involved in degrading different components of plant cell walls. Functional redundancy appears to exist among T2S-secreted proteins because significant effects on virulence are observed only in strains in which multiple secreted proteins are mutated. Several T2S-secreted proteins have been shown to induce plant defense responses, including hypersensitive response-like reactions. Bacterial pathogens can suppress these defense responses, and recent results indicate that suppression is mediated through the type three secretion system.


Assessments of the effects of nicotine and ketamine using tyrosine hydroxylase-green fluorescent protein transgenic zebrafish as biosensors.
Transgenic zebrafish are a common vertebrate model system for the study of addictive behavior. In the present study, plasmid constructs containing green fluorescent protein (GFP) and the promoter of tyrosine hydroxylase (TH), a key synthetic enzyme for catecholamines, were produced. The TH-GFP constructs were microinjected into zebrafish embryonic cells. Three days post-fertilization, GFP began expressing in distinct catecholaminergic areas. The TH-GFP transgenic zebrafish were employed as live biosensors to test the effects of the commonly abused drugs nicotine and ketamine. First, locomotion assays were used to study the general excitatory effects of the drugs. Maximal locomotor activity was obtained after treatment with a high concentration of nicotine (10 μM), but with a much lower concentration of ketamine (0.1 μM). Second, TH protein levels in zebrafish brains were assessed by Western blot. TH protein levels were significantly increased, with maximal protein levels found after treatment with the same drug concentrations that gave maximal locomotor activity. Importantly, analysis of GFP in the zebrafish catecholaminergic areas revealed the same expression patterns as was obtained by Western blot. The present results indicate that increased locomotor activity can be correlated to TH protein expression, as indicated by Western blot and expression of TH-GFP. We have shown that TH-GFP expression is a reliable method to show the effects of drugs on TH expression that may be employed as a novel high-throughput live biosensor for screening drugs of abuse.


Growth trajectories of maintenance variables related to refractory eating disorders in youth.
Despite decades of eating disorder (ED) research, studies of factors involved in long-term EDs are still lacking. This longitudinal study investigated the role of maintenance variables in a transdiagnostic adolescent ED sample. Participants included 275 adolescents who underwent specialized ED treatment. Hierarchical linear modeling confirmed a significant growth pattern of maintenance factors, wherein there was initial increase, then a decline during treatment, followed by a slight rebound post-treatment. Refractory status did not predict the variability in maintenance curves, suggesting that although this growth pattern existed, requiring a second treatment encounter did not explain the differences found in these patterns.


Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling.
Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB. HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB. In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.


High diversity in CMA3/DAPI-banding patterns in Heteropterans.
Heteroptera is the most numerous and diverse suborder of Hemiptera, with about 38,000 species. This diversity also involves cytogenetic features, including chromosome number and a sex determining system. Information about heterochromatin occurrence and distribution is scarce in heteropterans, but still, there is some evidence of variability. We determined the chromosome number and CMA3/DAPI-banding pattern of 179 individuals of 25 heteropteran species from Brazil. Eight species of Pentatomidae exhibited a constant chromosome number (2n = 12 + XY), but in Coreidae (12 species), Largidae (1 species), Rhopalidae (1 species), and Pyrrhocoridae (3 species), the numbers ranged from 2n = 10 + 2m + X0 to 2n = 24 + 2m + X0. Although there were no large differences in the chromosome size between species, the CMA3/DAPI-banding patterns differed markedly. Among the genera, species of Edessa, Spartocera, Hypselonotus, Phtia,Holhymenia and Euryophthalmus showed a large accumulation of heterochromatin, while the other species exhibited few or no heterochromatic bands. In general, when heterochromatin was more accumulated, this occurred preferentially at terminal positions, except in Holhymenia histrio, which exhibited intercalary bands. This study made it possible to identify some chromosome rearrangements and to enhance our knowledge of the evolutionary mechanisms that determine karyotype differentiation in Heteroptera.


Tualang Honey Attenuates Noise Stress-Induced Memory Deficits in Aged Rats.
Ageing and stress exposure may lead to memory impairment while oxidative stress is thought to be one of the underlying mechanisms involved. This study aimed to investigate the potential protective effects of Tualang honey supplementation on memory performance in aged rats exposed to noise stress. Tualang honey supplementation was given orally, 200 mg/kg body weight for 28 days. Rats in the stress group were subjected to loud noise, 100 dB(A), 4 hours daily for 14 days. All rats were subjected to novel object recognition test for evaluation of memory performance. It was observed that the rats subjected to noise stress exhibited significantly lower memory performance and higher oxidative stress as evident by elevated malondialdehyde and protein carbonyl levels and reduction of antioxidant enzymes activities compared to the nonstressed rats. Tualang honey supplementation was able to improve memory performance, decrease oxidative stress levels, increase brain-derived neurotrophic factor (BDNF) concentration, decrease acetylcholinesterase activity, and enhance neuronal proliferation in the medial prefrontal cortex (mPFC) and hippocampus. In conclusion, Tualang honey protects against memory decline due to stress exposure and/or ageing via enhancement of mPFC and hippocampal morphology possibly secondary to reduction in brain oxidative stress and/or upregulation of BDNF concentration and cholinergic system.


Preclinical Evaluation of a Cabazitaxel Prodrug Using Nanoparticle Delivery for the Treatment of Taxane-Resistant Malignancies.
Taxane-based chemotherapeutics are clinically available as frontline treatment regimens for cervical cancer. However, drug resistance and life-threatening toxicity impair the clinical efficacy of taxanes, so more effective and less toxic therapeutic modalities are urgently needed. Cabazitaxel has attracted increasing interest due to its potential to circumvent the drug resistance by taxanes. We previously showed that tethering docosahexaenoic acid (DHA) to cabazitaxel enabled the prodrug to self-assemble into nanoparticles in water. Despite this encouraging finding, the DHA-cabazitaxel conjugate formulation requires further optimization to enhance nanoparticle retention and tumor delivery. We here integrated this conjugate into amphiphilic poly(ethylene glycol)-block-poly(D,L-lactic acid) copolymers to assemble dCTX NPs The nanoparticle abrogated P-glycoprotein-mediated resistance in cancer cells. In a docetaxel-resistant cervical tumor xenograft-bearing mouse model, the efficacy was augmented by the nanotherapy when compared with solution-based free drugs (i.e., docetaxel and cabazitaxel). Dose intensification of dCTX NPs markedly suppressed the tumor growth in this model. Detailed studies revealed that systemic toxicity was alleviated, and MTD of dCTX NPs was at least 3 times higher than that of free cabazitaxel in animals, which may enable dose increases for clinical studies. In conclusion, the new formulation addresses essential requirements in terms of the stability, safety, and translational capacity for initiating early-phase clinical trials.


Targeting apoptosis pathways in cancer and perspectives with natural compounds from mother nature.
Although the incidences are increasing day after day, scientists and researchers taken individually or by research group are trying to fight against cancer by several ways and also by different approaches and techniques. Sesquiterpenes, flavonoids, alkaloids, diterpenoids, and polyphenolic represent a large and diverse group of naturally occurring compounds found in a variety of fruits, vegetables, and medicinal plants with various anticancer properties. In this review, our aim is to give our perspective on the current status of the natural compounds belonging to these groups and discuss their natural sources, their anticancer activity, their molecular targets, and their mechanism of actions with specific emphasis on apoptosis pathways, which may help the further design and conduct of preclinical and clinical trials. Unlike pharmaceutical drugs, the selected natural compounds induce apoptosis by targeting multiple cellular signaling pathways including transcription factors, growth factors, tumor cell survival factors, inflammatory cytokines, protein kinases, and angiogenesis that are frequently deregulated in cancers and suggest that their simultaneous targeting by these compounds could result in efficacious and selective killing of cancer cells. This review suggests that they provide a novel opportunity for treatment of cancer, but clinical trials are still required to further validate them in cancer chemotherapy.


National practice recommendations for hematuria: how to evaluate in the absence of strong evidence?
Hematuria is one of the most common conditions confronting clinical urologists and is present in many genitourinary pathology conditions. Although researchers have studied hematuria symptoms in an effort to determine the best diagnostic pathway, the existing lack of scientific evidence has created variations in clinical practice. The literature does not provide enough evidence to significantly alter the need to assess these patients. Consequently, many patients with microscopic or gross hematuria undergo low-yield workups that include invasive testing and imaging with radiation. In 2007, a national group of Kaiser Permanente (KP) urology chiefs agreed that national practice recommendations were needed to address existing variations in the management and workup of hematuria. Using a KP guideline methodology, the group reached a consensus agreement on the following recommendations: 1) referral to urology is recommended for all people with gross hematuria or high-grade hematuria (>50 red blood cells per high-power field [RBCs/HPF]) on a single urinalysis (UA); 2) referral to urology and urologic evaluation is recommended for men or women with asymptomatic microscopic hematuria or symptomatic hematuria that produces >3 RBCs/HPF on two of three properly performed and collected urinalyses; and 3) voided urinary cytology should be eliminated from asymptomatic hematuria screening protocol. The test is not sensitive enough to obviate further workup if findings are negative, and elimination of this screening test is estimated to save millions of dollars across the US. Hematuria on a UA should be reported as 0 to 3 RBC/HPF, 4 to 10 RBC/HPF, 11 to 25 RBC/HPF, 26 to 50 RBC/HPF, >50 RBC/HPF, or gross hematuria. This approach will also reduce radiation exposure.


The meaning of autonomy when living with dementia: A Q-method investigation.
Sensitivity to the rights of people with dementia is a key principle cited in the World Health Organisation's global action plan on dementia. Some critics question whether rights-based approaches embody loose and ill-defined ideas incapable of bringing about meaningful change. Exercising the right to autonomy is considered a core problem for people living with dementia. The tradition of individual sovereignty dominates ideas about autonomy, although the person as an individual is not a cross-culturally universal concept. This study explored the viewpoints of people with dementia and family carers regarding the meaning of autonomy with a view to informing rights-based practice. Twenty participants, people living with dementia and family carers, each conducted a Q-sort of statements regarding the meaning of autonomy. A by-person factor analysis was used to identify patterns in how the range of statements about autonomy were ranked. Three factors emerged: retaining independence and self-expression, accepting dependence but being included and opportunity for connection. There was some agreement across these different views regarding the importance of being given time to think before making decisions and being kept active. This study highlights the need for a person-centred approach to supporting people with dementia to claim their rights and the importance of adopting a stance of curiosity and critical thinking in rights-based training and professional practice. The findings suggest a variety of meaningful stories of autonomy and the possibility of further developing existing rights-based frameworks for dementia care.


Gianotti-Crosti syndrome and human immunodeficiency virus infection.
Patients with Gianotti-Crosti syndrome (GCS) present with a distinctive self-limiting acral papular or papulovesicular eruption associated with an underlying viral illness. Gianotti-Crosti syndrome in patients infected with human immunodeficiency virus has not been previously reported. We report on two children infected with human immunodeficiency virus who had GCS. Both patients had clinical and histopathologic findings characteristic of GCS. The first patient had evidence of prior infection with cytomegalovirus, without evidence of active viral illness. The second patient had evidence of subclinical infection with cytomegalovirus, positive hepatitis C antibody, and active infection with Mycobacterium avium-intracellulare at the time the skin eruption began. We call attention to a previously unreported skin eruption, GCS, in the setting of human immunodeficiency virus infection and emphasize that determining the etiologic factors for human immunodeficiency virus-associated GCS will be difficult; such patients will probably have a variety of clinical and subclinical infections that complicate this issue.


Recovery of neuronal function after prolonged cerebral ischemia.
Cats were submitted to complete cerebral ischemia by clamping the innominate and subclavian arteries and simultaneously lowering the systemic blood pressure. Neuronal function was assessed by recording the electroencephalogram and the anti- and orthodromic activation of the pyramidal tract. A full recovery of the pyramidal response and even of evoked electroencephalographic activity occurred after ischemia of more than 1 hour's duration.


Asthma prescription patterns for children: can GPs do better?
Assessing prescription patterns of asthma medication for children is helpful to optimize prescribing by general practitioners (GPs). The aim was to explore prescription patterns in children with physician-diagnosed asthma and its determinants in general practice. We used the Second Dutch National Survey of General Practice (DNSGP-2) with children aged 0-17 years registered in 87 general practices. All children with at least one asthma prescription were included (n = 2993). Prescription rates and prescription of continuous (≥3 prescriptions/year) versus intermittent asthma medication were calculated. Data, including several GP characteristics, were analysed using multivariate logistic regression accounting for clustering within practices. During one year, 16% of the children with physician-diagnosed asthma (n = 3562) received no asthma medication. Of the 2993 children with asthma receiving asthma medication (on average 2.9 prescriptions/year), 61% received one or two prescriptions, 39% received three or more. Continuous medication with a bronchodilator and/or a corticosteroid was prescribed in 22% of these children. One out of 5 children receiving continuous medication was prescribed a bronchodilator only. In 7.5% of the prescriptions, asthma medications other than bronchodilators or corticosteroids were prescribed. Prescribing asthma medication varied widely between practices, but none of the children and GP determinants had an independent effect on prescribing continuous versus intermittent medication. In general practice, the annual number of asthma prescriptions per child with asthma is relatively low. One in 20 children is prescribed bronchodilators only continuously, indicating room for improvement. Child and GP characteristics cannot be used for targeting educational efforts.


Association Between Resistance to Cerebrospinal Fluid Flow Near the Foramen Magnum and Cough-Associated Headache in Adult Chiari Malformation Type I.
Cough-associated headaches (CAHs) are thought to be distinctive for Chiari malformation type I (CMI) patients and have been shown to be related to the motion of cerebrospinal fluid (CSF) near the foramen magnum (FM). We used computational fluid dynamics (CFD) to compute patient-specific resistance to CSF motion in the spinal canal for CMI patients to determine its accuracy in predicting CAH. Fifty-one symptomatic CMI patients with cerebellar tonsillar position (CTP) ≥ 5 mm were included in this study. The patients were divided into two groups based on their symptoms (CAH and non-CAH) by review of the neurosurgical records. CFD was utilized to simulate CSF motion, and the integrated longitudinal impedance (ILI) was calculated for all patients. A receiver operating characteristic (ROC) curve was evaluated for its accuracy in predicting CAH. The ILI for CMI patients with CAH (776 dyn/cm5, 288-1444 dyn/cm5; median, interquartile range) was significantly larger compared to non-CAH (285 dyn/cm5, 187-450 dyn/cm5; p = 0.001). The ILI was more accurate in predicting CAH in CMI patients than the CTP when the comparison was made using the area under the ROC curve (AUC) (0.77 and 0.70, for ILI and CTP, respectively). ILI ≥ 750 dyn/cm5 had a sensitivity of 50% and a specificity of 95% in predicting CAH. ILI is a parameter that is used to assess CSF blockage in the spinal canal and can predict patients with and without CAH with greater accuracy than CTP.


The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells.
In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infection-related complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies. We investigated the impact of antibiotics on the therapeutic outcomes of cyclophosphamide (CTX) chemotherapy and adoptive T-cell therapy (ACT) where CTX was used as the host-conditioning regimen in mice. We show that antibiotic prophylaxis dampened the endogenous T cell responses elicited by CTX, and reduced the efficacy of CTX against B-cell lymphoma. In the ACT setting, antibiotics administration impaired the therapeutic effects of adoptively transferred tumor-specific CD4+ T cells in mice with implanted colorectal tumors. In contrast, long-term antibiotic exposure did not affect the efficacy of ACT using CD19-targeting chimeric antigen receptor (CAR) T cells in mice with systemic B-cell lymphoma, although it correlated with prolonged CAR expression and sustained B-cell aplasia. Our study demonstrates that chemoimmunotherapies may have variable reliance on intestinal microbiota for T cell activation and function, and thus have different sensitivities to antibiotic prophylaxis. These findings may have implications for the judicial use of antibiotics in cancer patients receiving chemoimmunotherapies.


Non-nutritive sweeteners for diabetes mellitus.
Products sweetened with non-nutritive sweeteners (NNS) are widely available. Many people with type 1 or type 2 diabetes use NNS as a replacement for nutritive sweeteners to control their carbohydrate and energy intake. Health outcomes associated with NNS use in diabetes are unknown. To assess the effects of non-nutritive sweeteners in people with diabetes mellitus. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Scopus, the WHO ICTRP, and ClinicalTrials.gov. The date of the last search of all databases (except for Scopus) was May 2019. We last searched Scopus in January 2019. We did not apply any language restrictions. We included randomised controlled trials (RCTs) with a duration of four weeks or more comparing any type of NNS with usual diet, no intervention, placebo, water, a different NNS, or a nutritive sweetener in individuals with type 1 or type 2 diabetes. Trials with concomitant behaviour-changing interventions, such as diet, exercise, or both, were eligible for inclusion, given that the concomitant interventions were the same in the intervention and comparator groups. Two review authors independently screened abstracts, full texts, and records retrieved from trials registries, assessed the certainty of the evidence, and extracted data. We used a random-effects model to perform meta-analysis, and calculated effect estimates as risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs). We assessed risk of bias using the Cochrane 'Risk of bias' tool and the certainty of evidence using the GRADE approach. We included nine RCTs that randomised a total of 979 people with type 1 or type 2 diabetes. The intervention duration ranged from 4 to 10 months. We judged none of these trials as at low risk of bias for all 'Risk of bias' domains; most of the included trials did not report the method of randomisation. Three trials compared the effects of a dietary supplement containing NNS with sugar: glycosylated haemoglobin A1c (HbA1c) was 0.4% higher in the NNS group (95% CI -0.5 to 1.2; P = 0.44; 3 trials; 72 participants; very low-certainty evidence). The MD in weight change was -0.1 kg (95% CI -2.7 to 2.6; P = 0.96; 3 trials; 72 participants; very low-certainty evidence). None of the trials with sugar as comparator reported on adverse events. Five trials compared NNS with placebo. The MD for HbA1c was 0%, 95% CI -0.1 to 0.1; P = 0.99; 4 trials; 360 participants; very low-certainty evidence. The 95% prediction interval ranged between -0.3% and 0.3%. The comparison of NNS versus placebo showed a MD in body weight of -0.2 kg, 95% CI -1 to 0.6; P = 0.64; 2 trials; 184 participants; very low-certainty evidence. Three trials reported the numbers of participants experiencing at least one non-serious adverse event: 36/113 participants (31.9%) in the NNS group versus 42/118 participants (35.6%) in the placebo group (RR 0.78, 95% CI 0.39 to 1.56; P = 0.48; 3 trials; 231 participants; very low-certainty evidence). One trial compared NNS with a nutritive low-calorie sweetener (tagatose). HbA1c was 0.3% higher in the NNS group (95% CI 0.1 to 0.4; P = 0.01; 1 trial; 354 participants; very low-certainty evidence). This trial did not report body weight data and adverse events. The included trials did not report data on health-related quality of life, diabetes complications, all-cause mortality, or socioeconomic effects. There is inconclusive evidence of very low certainty regarding the effects of NNS consumption compared with either sugar, placebo, or nutritive low-calorie sweetener consumption on clinically relevant benefit or harm for HbA1c, body weight, and adverse events in people with type 1 or type 2 diabetes. Data on health-related quality of life, diabetes complications, all-cause mortality, and socioeconomic effects are lacking.


Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation.
The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.


Russian isolates of potato spindle tuber viroid.
Forty PSTVd isolates collected from five regions of Russia (North-western, Central, Volga region, Northern Caucasus and the Far East) were sequenced during 2006-2008. All isolates lacked the adenine residue present at position 123 of the type strain; i.e., PSTVd-intermediate (GenBank V01465). Nineteen Russian isolates also contained an adenosine --> cytosine substitution at position 120. Twenty two additional unique changes were also observed in one or more of the isolates sequenced.


Tissue damage and haematophagia due to praniza larvae (Isopoda: Gnathiidae) in some aquarium seawater teleosts.
Over a 5 yr period, severe infestations due to Gnathia vorax larvae affecting different teleosts have been registered at the Civic Aquarium of Messina, Italy. Here, the damage caused by these parasites is evaluated from a macroscopical and histopathological point of view. We also attempt to evaluate the amount of blood sucked up by a single parasite and make some observations about the haematophagia. The histopathological changes confirm mucosal electrolytic failure as the main problem, even though the mean value of blood sucked up by a single parasite, about 1.9 mg, suggests that haematophagia may play an important role in the pathogenesis of such infestation. In conclusion, it was found that the G. vorax larvae caused 2-fold damage that was responsible for the death of the fish. Little by little, the parasitic problem was successfully removed by washing the tank, using fresh water rather than costly and dangerous chemotherapeutans.


Level of patient comfort and measurement reproducibility of three different probes: A cross-sectional study.
To determine the comfort level and reproducibility assessment of the probing pocket depth obtained with three different probes. A cross-sectional clinical study was conducted in accordance with the STROBE standards. Three different types of periodontal probes were selected: (1) University of North Carolina (UNC) probe, (2) World health organization (WHO) probe and (3) UNC12 COLORVUE probe. Three experienced and calibrated periodontists performed periodontal clinical assessments (probing depth) and pain assessment with the visual analogue scale (VAS). The clinical evaluations were carried out in 13 volunteers who attended the dental clinic of the Universidad Científica del Sur (Lima, Peru). A total of 2106 periodontal clinical measurements were obtained (702 measurements per examiner). Each examiner evaluated 234 sites for each type of probe. When patient comfort values during the periodontal evaluation performed with the 3 types of probes were compared, the patients evaluated with the UNC12 COLORVUE probe perceived less pain with a mean value of 0.61, followed by the WHO probe and the UNC probe. When evaluating the clinical measurements, the UNC probe was observed to obtain the greatest mean depth on probing 1.4 + 0.5 mm, while with the UNC12 Colorvue probe, the values obtained were 1.1 + 0.3 mm, and with the WHO probe, 1.2 + 0.4 mm. Based on the periodontal probe used, experience of the examiner and the patient, we can conclude that the UNC12 Colorvue probe was the instrument that promoted the greatest comfort or the slightest response to pain, followed by the WHO probe. However, the use of the WHO probe resulted in obtaining the lowest reproducibility among depths on probing. The UNC probe produced the highest response to pain in the patients.


PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations.
Single nucleotide variants represent a prevalent form of genetic variation. Mutations in the coding regions are frequently associated with the development of various genetic diseases. Computational tools for the prediction of the effects of mutations on protein function are very important for analysis of single nucleotide variants and their prioritization for experimental characterization. Many computational tools are already widely employed for this purpose. Unfortunately, their comparison and further improvement is hindered by large overlaps between the training datasets and benchmark datasets, which lead to biased and overly optimistic reported performances. In this study, we have constructed three independent datasets by removing all duplicities, inconsistencies and mutations previously used in the training of evaluated tools. The benchmark dataset containing over 43,000 mutations was employed for the unbiased evaluation of eight established prediction tools: MAPP, nsSNPAnalyzer, PANTHER, PhD-SNP, PolyPhen-1, PolyPhen-2, SIFT and SNAP. The six best performing tools were combined into a consensus classifier PredictSNP, resulting into significantly improved prediction performance, and at the same time returned results for all mutations, confirming that consensus prediction represents an accurate and robust alternative to the predictions delivered by individual tools. A user-friendly web interface enables easy access to all eight prediction tools, the consensus classifier PredictSNP and annotations from the Protein Mutant Database and the UniProt database. The web server and the datasets are freely available to the academic community at http://loschmidt.chemi.muni.cz/predictsnp.


Community based health insurance scheme: Preferences of rural dwellers of the federal capital territory Abuja, Nigeria.
In 2010, community based health insurance scheme (CBHIS) was launched in the Federal Capital Territory (FCT) of Nigeria. Little is known about the preferences and perception of the rural dwellers of the FCT about the scheme. This study aimed to determine the preferences of healthcare consumers towards CBHIS in FCT. A descriptive cross sectional study of 287 household heads was done. Systematic random sampling was used. Information was collected using a semi-structured, interviewer administered questionnaire. Data was analysed with SPSS version 21. Male respondents were 175 (61%), 242 (84.3%) were aware of the existence of CBHIS, 126 (82%) also enrolled their dependents. Annual payment of health insurance premium was preferred by 91 (59.9%) of enrolled respondents, 92 (60.1%) enrolled in the scheme because they perceived it to be a cheap way to access healthcare. No proper understanding was the reason why 33 (28.4%) of those aware of the scheme did not enroll themselves or their dependents. Only 124 (55.1%) were satisfied with the overall services provided to them by their health care provider (HCP). More community enlightenment on CBHIS is required. There is a need to factor in the preferences of the community members into the FCTCBHIS to determine what community members are willing to pay for their healthcare premium and how making contributions will be convenient for them.


Stimulation of phosphatidylcholine synthesis by activators of protein kinase C is dissociable from increased phospholipid hydrolysis.
The aim of this study was to clarify the relationship between the stimulatory effects of protein kinase C activators, including phorbol 12-myristate 13-acetate (PMA) and bryostatin, on the hydrolysis of phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) and on PtdCho synthesis. The cell lines used were selected because of their differential responses to protein kinase C activators and included rat-1 fibroblasts, untransformed and A-raf-transformed NIH 3T3 fibroblasts and human HL60 leukaemia cells. Exposure of rat-1 and NIH 3T3 fibroblasts to 100 nM-PMA stimulated phospholipase D-mediated hydrolysis of phospholipids about 2- and 6-fold respectively. In contrast, 100 nM-PMA had similar (2.5-3.0-fold) stimulatory effects on PtdCho synthesis in these cell lines. In the untransformed NIH 3T3 cells, both PMA and bryostatin stimulated both phospholipid hydrolysis and PtdCho synthesis, with 100 nM-bryostatin being somewhat less potent than 100 nM-TPA. In contrast, in A-raf-transformed NIH 3T3 cells or in HL60 cells, only TPA, but not bryostatin, stimulated PtdCho synthesis. In these transformed cells, bryostatin had 3-fold, or higher, stimulatory effects on phospholipid hydrolysis. Addition of ionomycin, a Ca2(+)-elevating agent, partially restored the stimulatory effect of bryostatin on PtdCho synthesis, but it failed to modify the effect of bryostatin on phospholipid hydrolysis. These data indicate that increased phospholipid hydrolysis is not necessarily associated with increased PtdCho synthesis.


Community-based infant hearing screening for early detection of permanent hearing loss in Lagos, Nigeria: a cross-sectional study.
To determine the feasibility and effectiveness of a community-based universal infant hearing screening programme for detecting permanent congenital and early-onset hearing loss (PCEHL) in Lagos, Nigeria. This is a cross-sectional study in which all infants aged 3 months or under attending four bacille Calmette-Guérin (BCG) immunization clinics accounting for over 75% of the BCG coverage in the study location were screened by community health workers between July 2005 and April 2006. Screening followed a two-stage protocol involving transient evoked otoacoustic emissions and automated auditory brainstem responses. The main outcome measures were screening coverage, referral rates, return rates for second-stage screening and evaluation, yield and age at PCEHL diagnosis. In total, 2003 (88%) of 2277 eligible infants attending the four BCG clinics were successfully screened between July 2005 and April 2006 at a mean age of 17.7 days, with no parent declining screening. The majority (55.2%) were born outside a hospital and, of such infants, 77% were born in traditional herbal maternity homes. The overall referral rate for diagnostic evaluation was 4.1%. Only 61% (50/82) of those referred returned for evaluation, and 45 of them were confirmed with PCEHL. Additionally, 11 infants who had previously passed the first screening stage were also found to have PCEHL, resulting in a yield of 28 per 1000 (56/2003). The mean age at diagnosis was 51 days. The sensitivity, specificity and positive predictive value of the first screening stage were 80.4%, 99.7% and 90.0%, respectively. The positive likelihood ratio was 268, while the negative likelihood ratio was 0.2. Routine hearing screening of infants attending BCG immunization clinics by community health workers was feasible and effective for the early detection of PCEHL in Lagos, Nigeria. However, an efficient tracking and follow-up system is needed to improve return rates for second-stage screening and diagnostic evaluation.


Prevalence of Chlamydial Infections in Fattening Pigs and Their Influencing Factors.
Chlamydial infections in pigs are associated with respiratory disease, diarrhea, conjunctivitis and other pathologies. The aim of this study was to define the prevalence of Chlamydiaceae in Swiss fattening pigs by applying sensitive and specific detection methods and to correlate prior antibiotic treatment and farm related factors with differences in prevalence. Conjunctival and fecal swabs were collected from 636 pigs in 29 Swiss fattening pig farms with and without antibiotic treatment, at the beginning and the end of the fattening period. The swabs were screened by real-time PCR for Chlamydiaceae. For the chlamydial detection and species-identification, a DNA-microarray analysis was performed. All farms were positive for Chlamydiaceae with 94.3 and 92.0% prevalence in fecal swabs as well as 45.9 and 32.6% in conjunctival swabs at the first and second time points, respectively. Antibiotic treatment could not clear the infection on herd level. Potential contact with wild boars was a significant risk factor, while hygiene criteria did not influence chlamydial prevalence. A correlation of chlamydial positivity to diarrhea, but not to conjunctivitis was evident. Chlamydia suis was the predominant species. Mixed infections with C. suis and C. pecorum were common, with a substantial increase in C. pecorum positivity at the end of the fattening period, and this finding was associated with ruminant contact. C. abortus was detected in one conjunctival swab. In this study, C. suis inhabited the intestinal tract of nearly all examined pigs, implying a long-term infection. C. pecorum was also common and might be transmitted to pigs by ruminants.


Kinetic analysis of a molecular model of the budding yeast cell cycle.
The molecular machinery of cell cycle control is known in more detail for budding yeast, Saccharomyces cerevisiae, than for any other eukaryotic organism. In recent years, many elegant experiments on budding yeast have dissected the roles of cyclin molecules (Cln1-3 and Clb1-6) in coordinating the events of DNA synthesis, bud emergence, spindle formation, nuclear division, and cell separation. These experimental clues suggest a mechanism for the principal molecular interactions controlling cyclin synthesis and degradation. Using standard techniques of biochemical kinetics, we convert the mechanism into a set of differential equations, which describe the time courses of three major classes of cyclin-dependent kinase activities. Model in hand, we examine the molecular events controlling "Start" (the commitment step to a new round of chromosome replication, bud formation, and mitosis) and "Finish" (the transition from metaphase to anaphase, when sister chromatids are pulled apart and the bud separates from the mother cell) in wild-type cells and 50 mutants. The model accounts for many details of the physiology, biochemistry, and genetics of cell cycle control in budding yeast.


When redundant on-screen text in multimedia technical instruction can interfere with learning.
It is frequently assumed that presenting the same material in written and spoken form benefits learning and understanding. The present work provides a theoretical justification based on cognitive load theory, and empirical evidence based on controlled experiments, that this assumption can be incorrect. From a theoretical perspective, it is suggested that if learners are required to coordinate and simultaneously process redundant material such as written and spoken text, an excessive working memory load is generated. Three experiments involving a group of 25 technical apprentices compared the effects of simultaneously presenting the same written and auditory textual information as opposed to either temporally separating the two modes or eliminating one of the modes. The first two experiments demonstrated that nonconcurrent presentation of auditory and visual explanations of a diagram proved superior, in terms of ratings of mental load and test scores, to a concurrent presentation of the same explanations when instruction time was constrained. The 3rd experiment demonstrated that a concurrent presentation of identical auditory and visual technical text (without the presence of diagrams) was significantly less efficient in comparison with an auditory-only text. Actual or potential applications of this research include the design and evaluation of multimedia instructional systems and audiovisual displays.


Internal impingement of the shoulder: a clinical and arthroscopic analysis.
Internal impingement was first described by Walch in 1992 and defined as contact between the supraspinatus tendon and posterior-superior glenoid rim with the shoulder in the cocked, throwing position of 90 degrees of abduction and maximum external rotation. The hypothesis of the study was that this contact may be seen in patients who are not throwing athletes nor in those who have instability. One hundred five consecutive patients who underwent shoulder arthroscopy were prospectively studied with preoperative history and physical examination. All patients underwent general anesthesia and arthroscopy with a standard posterior portal. With the patient under arthroscopy the arm was placed in abduction and external rotation until contact was made or until full elevation was reached. Eighty-five percent (N = 90) of the patients made contact between the rotator cuff and glenoid rim at an average of 95 degrees of abduction and 74 degrees of external rotation. No statistically significant relationship was seen (P > .05) between the position of contact at internal impingement and mechanism of injury, throwing versus nonthrowing, instability, rotator cuff tear, preoperative external rotation, or preoperative impingement signs. The intraoperative finding of contact of the rotator cuff to the posterosuperior glenoid with the arm in abduction and external rotation can occur in a wide spectrum of shoulder disease and is not limited to the throwing athlete. Not all patients with increased laxity and instability demonstrate this contact, suggesting that these factors may not be essential for internal impingement.


Metabolic implications of reduced heart-type fatty acid binding protein in insulin resistant cardiac muscle.
Insulin resistance is characterized by elevated rates of cardiac fatty acid utilization resulting in reduced efficiency and cardiomyopathy. One potential therapeutic approach is to limit the uptake and oxidation of fatty acids. The aims of this study were to determine whether a quantitative reduction in heart-type fatty acid binding protein (FABP3) normalizes cardiac substrate utilization without altering cardiac function. Transgenic (FABP3(+/-)) and wild-type (WT) littermates were studied following low fat (LF) or high fat (HF) diets, with HF resulting in obese, insulin-resistant mice. Cardiovascular function (systolic blood pressure, % fractional shortening) and heart dimension were measured at weaning and every month afterward for 3 mo. During this period cardiovascular function was the same independent of genotype and diet. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions in mice at 4 mo of age. Following 5 d recovery, mice underwent either a saline infusion or a hyperinsulinemic-euglycemic clamp (4 mU kg(-1) min(-1)). Indices of long chain fatty acid and glucose utilization (R(f), R(g); mumol g wet weight(-1) min(-1)) were obtained using 2-deoxy[(3)H]glucose and [(125)I]-15-rho-iodophenyl)-3-R,S-methylpentadecanoic acid. FABP3(+/-) had enhanced cardiac R(g) compared with WT during saline infusion in both LF and HF. FABP3(+/-) abrogated the HF-induced decrement in insulin-stimulated cardiac R(g). On a HF diet, FABP(+/-) but not WT had an increased reliance on fatty acids (R(f)) during insulin stimulation. In conclusion, cardiac insulin resistance and glucose uptake is largely corrected by a reduction in FABP3 in vivo without contemporaneous deleterious effects on cardiac function.


Intake and status of folate and related B-vitamins: considerations and challenges in achieving optimal status.
Folate and the metabolically related B-vitamins, vitamin B12 and riboflavin, have attracted much scientific and public health interest in recent years. Apart from a well established role in preventing neural tube defects (NTDs), evidence is emerging to support other potential roles for folate and/or related B-vitamins in protecting against cardiovascular disease (especially stroke), certain cancers, cognitive impairment and osteoporosis. However, typical folate intakes are sub-optimal, in that although adequate in preventing clinical folate deficiency (i.e. megaloblastic anaemia) in most people, they are generally insufficient to achieve a folate status associated with the lowest risk of NTDs. Natural food folates have a limited ability to enhance folate status as a result of their poor stability under typical cooking conditions and incomplete bioavailability when compared with the synthetic vitamin, folic acid (as found in supplements and fortified foods). Current folate recommendations to prevent NTDs (based primarily on folic acid supplementation) have been found to be ineffective in several European countries. In contrast, in North America and Chile, the policy of mandatory folic acid-fortification has proven itself in terms of lowering the prevalence of NTD, but remains controversial because of concerns regarding potential risks of chronic exposure to high-dose folic acid. In the case of vitamin B12, the achievement of an optimal status is particularly difficult for many older people because of the common problem of food-bound B12 malabsorption. Finally, there is evidence that riboflavin status is generally low in the UK population, and particularly so in younger women; this warrants further investigation.


Refractive index degeneration in older lenses: A potential functional correlate to structural changes that underlie cataract formation.
A major structure/function relationship in the eye lens is that between the constituent proteins, the crystallins and the optical property of refractive index. Structural breakdown that leads to cataract has been investigated in a number of studies; the concomitant changes in the optics, namely increases in light attenuation have also been well documented. Specific changes in the refractive index gradient that cause such attenuation, however, are not well studied because previous methods of measuring refractive index require transparent samples. The X-ray Talbot interferometric method using synchrotron radiation allows for measurement of fine changes in refractive index through lenses with opacities. The findings of this study on older human lenses show disruptions to the refractive index gradient and in the refractive index contours. These disruptions are linked to location in the lens and occur in polar regions, along or close to the equatorial plane or in lamellar-like formations. The disruptions that are seen in the polar regions manifest branching formations that alter with progression through the lens with some similarity to lens sutures. This study shows how the refractive index gradient, which is needed to maintain image quality of the eye, may be disturbed and that this can occur in a number of distinct ways. These findings offer insight into functional changes to a major optical parameter in older lenses. Further studies are needed to elicit how these may be related to structural degenerations reported in the literature.


ADAM28 is a serological and histochemical marker for non-small-cell lung cancers.
ADAM28 (a disintegrin and metalloproteinase 28) is over-expressed in non-small-cell lung cancer (NSCLC) with correlation to cancer cell proliferation, tumor size and lymph node metastasis. The present study was aimed to develop an enzyme-linked immunosorbent assay (ELISA) system for diagnosis and monitoring of NSCLC. Our ELISA specifically measured ADAM28, showing negligible cross-reactivity with other metalloproteinases. The ADAM28 level in the NSCLC tissue was remarkably 36.9-fold higher than that in the non-neoplastic lung tissue (p < 0.001). The serum level was significantly 4.6-fold higher in the NSCLC patients (5.41 +/- 8.62 ng/ml; n = 102) than in the control subjects (1.17 +/- 0.93 ng/ml; n = 20) (p < 0.001), and increased with progress of tumor stage (p < 0.001). The level was also significantly higher in the patients with recurrent carcinoma than the control (p < 0.001) and in the patients with lymph node metastasis than those without metastasis (p < 0.001). The sensitivity, false-negative rate and AUC for ADAM28 were better than those for carcinoembryonic antigen. The combination of both assays improved the sensitivity, specificity, false-positive and false-negative rates for NSCLC. There was a positive correlation between the ADAM28 level measured by ELISA system and the degree of immunostaining in the lung adenocarcinomas with a size of <or=20 mm in diameter. The adenocarcinoma patients showing the high immunohistochemical reaction exhibited a poorer disease-free survival than those with the lower immunoreactivity (n = 102; p < 0.05). These data demonstrate that our ELISA is specific and sensitive to monitor the levels of ADAM28 in the samples from NSCLC patients and suggest that ADAM28 is a useful serological and histochemical marker for NSCLC.


Role of norepinephrine in depression.
This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and the therapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletion studies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved in antidepressant action, but the specific impairment that underlies depression is unclear and is likely to vary among patients. Results from neurotransmitter depletion studies in depressed patients who have responded to treatment suggest that, while interactions between NE and 5-HT are likely, neither of these 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressant drugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability of NE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent on the availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic and serotonergic systems-such as mirtazapine-may be dependent on the availability of both neurotransmitters for their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjects or worsened depression in unmedicated symptomatic patients with major depression. This finding suggests that the cause of depression is more complex than just an alteration in the levels of 5-HT and/or NE. For some patients, depression may be more directly caused by dysfunction in brain areas or neuronal systems modulated by monoamine systems. We propose that antidepressant drugs may enhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependent but as yet undiscovered process, restore function to brain areas modulated by monoamine neurons. Future research should focus on understanding the adaptive changes that follow enhancement of synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus. Research investigating the neurobiology of depression may be more informed if the focus is shifted to investigating areas of the brain modulated by monoamine systems rather than the monoamine systems themselves.


Implementation of national guidelines for the prevention and treatment of overweight and obesity in children and adolescents: a phenomenographic analysis of public health nurses' perceptions.
To explore and describe how public health nurses (PHNs) perceive the implementation of national guidelines for the prevention and treatment of overweight and obesity among children and adolescents in well-baby clinics and school health services. An explorative descriptive design was carried out through individual interviews with 18 PHNs and analysed according to the phenomenographic tradition. Four implementation strategies were described and assigned a metaphor: the structured PHN, pragmatic PHN, critical PHN, and the resigned PHN. Competence, patient receptiveness, internal consensus, interdisciplinary collaboration, resources, and organizational embedding were the determinants identified that most frequently affect implementation, and these determinants were distributed at different levels of the organization. The extent of facilitation seemed to determine which implementation strategy would be used. How PHNs implemented the guidelines for overweight and obesity were affected by determinants at different organizational levels. Contextual facilitation of implementation seemed better in larger organizations, but factors such as leadership, drive, and experience compensated in smaller municipalities. The implementation of guidelines was hindered when the barriers exceeded the benefits.


Norepinephrine transporter is involved in down-regulation of beta1-adrenergic receptors caused by adjuvant arthritis.
Inflammation in forms of rheumatoid and experimental arthritis cause not only joint pain but also excessive cardiovascular mortality. The condition also reduces response to calcium channel and beta-adrenergic (beta1-AR) antagonists. For calcium channel inhibitors, the reduced response is shown to be due to the reduced expression of target proteins. Hydroxymethylglutaryl CoA reductase inhibitors (statins) restore response to propranolol and verapamil. We tested the effect of adjuvant arthritis on the norepinephrine (NE) transporter (NET) density since altered sympathetic nervous system innervation has been observed in rheumatoid arthritis. Male Sprague-Dawley rats were divided into the following groups: Healthy/Placebo, Healthy/Statin, Pre-AA/Placebo, and Pre-AA/Statin (n=7-8/group). On Day 0, to the Pre-AA and Healthy groups, was injected Mycobacterium butyricum or saline, respectively. On Days 4-8, Statin and Placebo groups received either pravastatin (6 mg/kg) or placebo twice daily, respectively. On day 8, heart and blood samples were collected. The density of NET and 1-AR in heart homogenate; NE in plasma and heart and inflammatory mediators (nitrite and interferon-gamma) in serum were determined. Inflammation was associated with a significant reduction in both beta1-AR and NET density with a positive correlation between the two proteins (r=0.978, p<0.0001). The down-regulating effect of inflammation was not reversed by pravastatin. Inflammation had no significant effect on the plasma or heart NE concentration. The close relations of NET and beta1-AR implicates altered sympathetic innervation and/or local NE handling in pharmacotherapeutic desensitization observed in arthritis.


Discordance between WMS-III Word Lists subtest and RAVLT scores in older patients: four case examples.
To examine the adequacy of the WMS-III in the identification of memory deficits in older individuals, we administered the Word Lists subtest, along with a comparison measure, the Rey Auditory Verbal Learning Test (RAVLT), to four patients referred for assessment of dementia. Although the number of words recalled by the patients on the delayed trials of the Word Lists subtest and RAVLT were nearly identical, norms for the Word Lists subtest indicated that memory performance was within normal limits (i.e., low average or higher), while the RAVLT norms accurately characterized performance as impaired. We suspect that normative data for the WMS-III were compromised by inadvertent inclusion of older subjects with dementia or mild cognitive impairment. The findings from our cases call into question the use of the WMS-III Word Lists for older patients.


A two-year perspective: who may ease the burden of girls' loneliness in school?
Loneliness is negatively related to good health and wellbeing, especially among girls. There is little research, however, on factors that may ease the burdens of loneliness in the school setting. Thus, we explored the relationship between girls' loneliness and later school wellbeing adjusted for other adversities. Furthermore, we assessed the significance of having someone whom the girl trusted by investigating possible modifying influences on the addressed association. Altogether, 119 girls in grades 1-8 provided baseline data and answered the same set of questions two years later. Logistic regression models including perceived academic problems, victimisation by bullying, loneliness and trusted others were tested with bad versus good school wellbeing two years later as outcome using SPSS. In the multivariable analysis of loneliness, academic problems, and victimisation, loneliness was the only variable showing a strong and negative contribution to later school wellbeing. Next, demonstrated in separate models; the inclusion of having a trusted class advisor fully attenuated the association of loneliness with later school wellbeing. In contrast, other trusted teachers, trusted parents, or trusted students did not affect the association. Loneliness in girls strongly predicted school wellbeing two years later. However, having a class advisor whom the girl trusted to contact in hurtful situations clearly reduced the burden of loneliness. This finding highlights the clinical importance of stability, long-lasting relations, and trust that main teachers may represent for lonely girls.


Spatial regulation of intracellular pH in the ventricular myocyte.
In the cardiac myocyte, an adequate intracellular proton mobility is necessary for coupling sarcolemmal proton transport to bulk cytoplasm during intracellular pH regulation. It is also important for dissipating intracellular pH nonuniformity in response to local acid/base disturbances. Because cardiac myocytes have a high buffering capacity, intracellular H(+) mobility is low. Spatial H(i)+ movements occur via a mobile buffer shuttle that most likely involves intracellular dipeptides. In the present work with isolated ventricular myocytes, it is demonstrated that stimulating a large acid efflux on sarcolemmal Na(+)-H(+) exchange, results in spatial pH(i) gradients of up to 0.1 U. These may have important implications for pH-sensitive processes within the cell, such as contraction. By using computational modeling, it is shown that the gradients can be attributed to the low H(i)+ mobility. Computational modeling is also used to assess the importance of H(i)+ mobility in mediating local recovery of pH following an acidosis in a small region of the cell. Results indicate that local mechanisms for H(i)+ movement will be important in determining the global regulation of intracellular pH.


Switchable and spacing-tunable dual-wavelength thulium-doped silica fiber laser based on a nonlinear amplifier loop mirror.
A kind of switchable and spacing-tunable dual-wavelength thulium-doped silica fiber laser based on a nonlinear amplifier loop mirror is presented and experimentally demonstrated. By adjusting the polarization controllers (PCs), stable dual-wavelength operation is obtained at the 2 μm band. The optical signal-to-noise ratio (OSNR) is better than 56 dB. The wavelength tuning is performed by applying static strain into the fiber Bragg grating. A tuning range from 0 to 5.14 nm is achieved for the dual-wavelength spacing. By adjusting the PCs properly, the fiber laser can also operate in single-wavelength state with the OSNR for each wavelength more than 50 dB.


Steps, challenges and lessons in developing community mental health care.
This paper summarises our own accumulated experience from developing community-orientated mental health services in England and Italy over the last 20-30 years. From this we have provisionally concluded that the following issues are central to the development of balanced mental health services: a) services need to reflect the priorities of service users and carers; b) evidence supports the need for both hospital and community services; c) services need to be provided close to home; d) some services need to be mobile rather than static; e) interventions need to address both symptoms and disabilities; and f) treatment has to be specific to individual needs. In this paper we consider ten key challenges that often face those trying to develop community-based mental health services: a) dealing with anxiety and uncertainty; b) compensating for a possible lack of structure in community services; c) learning how to initiate new developments; d) managing opposition to change within the mental health system; e) responding to opposition from neighbours; f) negotiating financial obstacles; g) avoiding system rigidities; h) bridging boundaries and barriers; i) maintaining staff morale; and j) creating locally relevant ser- vices rather than seeking "the right answer" from elsewhere.


Constipation and Incident CKD.
Constipation is one of the most prevalent conditions in primary care settings and increases the risk of cardiovascular disease, potentially through processes mediated by altered gut microbiota. However, little is known about the association of constipation with CKD. In a nationwide cohort of 3,504,732 United States veterans with an eGFR ≥60 ml/min per 1.73 m2, we examined the association of constipation status and severity (absent, mild, or moderate/severe), defined using diagnostic codes and laxative use, with incident CKD, incident ESRD, and change in eGFR in Cox models (for time-to-event analyses) and multinomial logistic regression models (for change in eGFR). Among patients, the mean (SD) age was 60.0 (14.1) years old; 93.2% of patients were men, and 24.7% were diabetic. After multivariable adjustments, compared with patients without constipation, patients with constipation had higher incidence rates of CKD (hazard ratio, 1.13; 95% confidence interval [95% CI], 1.11 to 1.14) and ESRD (hazard ratio, 1.09; 95% CI, 1.01 to 1.18) and faster eGFR decline (multinomial odds ratios for eGFR slope <-10, -10 to <-5, and -5 to <-1 versus -1 to <0 ml/min per 1.73 m2 per year, 1.17; 95% CI, 1.14 to 1.20; 1.07; 95% CI, 1.04 to 1.09; and 1.01; 95% CI, 1.00 to 1.03, respectively). More severe constipation associated with an incrementally higher risk for each renal outcome. In conclusion, constipation status and severity associate with higher risk of incident CKD and ESRD and with progressive eGFR decline, independent of known risk factors. Further studies should elucidate the underlying mechanisms.


Procedural specificity in laparoscopic simulator training: protocol for a randomised educational superiority trial.
The use of structured curricula for minimally invasive surgery training is becoming increasingly popular. However, many laparoscopic training programs still use basic skills and isolated task training, despite increasing evidence to support the use of training models with higher functional resemblance, such as whole procedural modules. In contrast to basic skills training, procedural training involves several cognitive skills such as elements of planning, movement integration, and how to avoid adverse events. The objective of this trial is to investigate the specificity of procedural practice in laparoscopic simulator training. A randomised single-centre educational superiority trial. Participants are 96 surgical novices (medical students) without prior laparoscopic experience. Participants start by practicing a series of basic skills tasks to a predefined proficiency level on a virtual reality laparoscopy simulator. Upon reaching proficiency, the participants are randomised to either the intervention group, which practices two procedures (an appendectomy followed by a salpingectomy) or to the control group, practicing only one procedure (a salpingectomy) on the simulator. 1:1 central randomisation is used and participants are stratified by sex and time to complete the basic skills. Data collection is done at a surgical skills centre.The primary outcome is the number of repetitions required to reach a predefined proficiency level on the salpingectomy module. The secondary outcome is the total training time to proficiency. The improvement in motor skills and effect on cognitive load are also explored. The results of this trial might provide new knowledge on how the technical part of surgical training curricula should be comprised in the future. To examine the specificity of practice in procedural simulator training is of great importance in order to develop more comprehensive surgical curricula. ClinicalTrials.gov: NCT02069951.


Diversity of benthic biofilms along a land use gradient in tropical headwater streams, Puerto Rico.
The properties of freshwater ecosystems can be altered, directly or indirectly, by different land uses (e.g., urbanization and agriculture). Streams heavily influenced by high nutrient concentrations associated with agriculture or urbanization may present conditions that can be intolerable for many aquatic species such as macroinvertebrates and fishes. However, information with respect to how benthic microbial communities may respond to changes in stream ecosystem properties in relation to agricultural or urban land uses is limited, in particular for tropical ecosystems. In this study, diversity of benthic biofilms was evaluated in 16 streams along a gradient of land use at the Turabo watershed in Puerto Rico using terminal restriction fragment length polymorphism. Diversity indices and community structure descriptors (species richness, Shannon diversity, dominance and evenness) were calculated for both bacteria and eukaryotes for each stream. Diversity of both groups, bacteria and eukaryotes, did not show a consistent pattern with land use, since it could be high or low at streams dominated by different land uses. This suggests that diversity of biofilms may be more related to site-specific conditions rather than watershed scale factors. To assess this contention, the relationship between biofilm diversity and reach-scale parameters (i.e., nutrient concentrations, canopy cover, conductivity, and dissolved oxygen) was determined using the Akaike Information Criterion (AIC(c)) for small sample size. Results indicated that nitrate was the variable that best explained variations in biofilm diversity. Since nitrate concentrations tend to increase with urban land use, our results suggest that urbanization may indeed increase microbial diversity indirectly by increasing nutrients in stream water.


Case Study: Johns Hopkins Community Health Partnership: A model for transformation.
To address the challenging health care needs of the population served by an urban academic medical center, we developed the Johns Hopkins Community Health Partnership (J-CHiP), a novel care coordination program that provides services in homes, community clinics, acute care hospitals, emergency departments, and skilled nursing facilities. This case study describes a comprehensive program that includes: a community-based intervention using multidisciplinary care teams that work closely with the patient's primary care provider; an acute care intervention bundle with collaborative team-based care; and a skilled nursing facility intervention emphasizing standardized transitions and targeted use of care pathways. The program seeks to improve clinical care within and across settings, to address the non-clinical determinants of health, and to ultimately improve healthcare utilization and costs. The case study introduces: a) main program features including rationale, goals, intervention design, and partnership development; b) illness burden and social barriers of the population contributing to care challenges and opportunities; and c) lessons learned with steps that have been taken to engage both patients and providers more actively in the care model. Urban health systems, including academic medical centers, must continue to innovate in care delivery through programs like J-CHiP to meet the needs of their patients and communities.