Sulpiride augmentation for schizophrenia.
Sulpiride may be used in combination with other antipsychotic drugs in the hope of augmenting effectiveness - especially for those whose schizophrenia has proved resistant to treatment. To evaluate the effects of sulpiride augmentation versus monotherapy for people with schizophrenia. We searched the Cochrane Schizophrenia Group Trials Register (July 2009) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. All relevant randomised clinical trials (RCTs). We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a fixed-effect model. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. We included three short-term and one long-term trial (total N=221). All participants had schizophrenia that was either treatment-resistant or with prominent negative symptoms. All studies compared sulpiride plus clozapine with clozapine (+/- placebo), were small and at considerable risk of bias.Short-term data of 'no clinically significant response' in global state tended to favour sulpiride augmentation of clozapine compared with clozapine alone (n=193, 3 RCTs, RR 0.58 CI 0.3 to 1.09).People allocated to sulpiride plus clozapine had more movement disorders (n=70, 1 RCT, RR 48.24 CI 3.05 to 762.56) and an increase in serum prolactin (skewed data, 1 RCT), but less incidence of hypersalivation (n=162, 3 RCTs, RR 0.49 CI 0.29 to 0.83) and less weight gain (n=64, 1 RCT, RR 0.30 CI 0.09 to 0.99). The augmentation of clozapine by sulpiride also caused less appetite loss (n=70, 1 RCT, RR 0.09 CI 0.01 to 0.70, NNT 4 CI 4 to 12, Z=2.31, P=0.02) and less abdominal distension (n=70, 1 RCT, RR 0.10 CI 0.01 to 0.78, NNT 5 CI 4 to 19, Z=2.20, P=0.03).Long-term data showed no significant difference in global state (n=70, 1 RCT, RR 0.67 CI 0.42 to 1.08) and relapse (n=70, 1 RCT, RR 0.85 CI 0.5 to 1.3). Sulpiride plus clozapine is probably more effective than clozapine alone in producing clinical improvement in some people whose illness has been resistant to other antipsychotic drugs including clozapine. However, much more robust data are needed.


Amyotrophic Lateral Sclerosis and Occupational Exposures: A Systematic Literature Review and Meta-Analyses.
Objectives: We conducted a systematic literature review to identify studies fulfilling good scientific epidemiological standards for use in meta-analyses of occupational risk factors for amyotrophic lateral sclerosis (ALS). Methods: We identified 79 original publications on associations between work and ALS. The MOOSE (Meta-analysis Of Observational Studies in Epidemiology) and GRADE (Grading of Recommendations, Assessment, Development and Evaluations) guidelines were used to ensure high scientific quality, and reliable protocols were applied to classify the articles. Thirty-seven articles fulfilled good scientific standards, while 42 were methodologically deficient and thus were excluded from our meta-analyses. Results: The weighted relative risks for the various occupational exposures were respectively; 1.29 (95% confidence interval (CI): 0.97⁻1.72; six articles) for heavy physical work, 3.98 (95% CI: 2.04⁻7.77; three articles) for professional sports, 1.45 (95% CI: 1.07⁻1.96; six articles) for metals, 1.19 (95% CI: 1.07⁻1.33; 10 articles) for chemicals, 1.18 (95% CI: 1.07⁻1.31; 16 articles) for electromagnetic fields or working with electricity, and 1.18 (95% CI: 1.05⁻1.34; four articles) for working as a nurse or physician. Conclusions: Meta-analyses based only on epidemiologic publications of good scientific quality show that the risk of ALS is statistically significantly elevated for occupational exposures to excessive physical work, chemicals (especially pesticides), metals (especially lead), and possibly also to electromagnetic fields and health care work. These results are not explained by publication bias.


Seroprevalence of cytomegalovirus and rubella among pregnant women in western Sudan.
Maternal cytomegalovirus (CMV) and rubella infections have adverse neonatal outcomes. Basic epidemiological data concerning CMV and rubella is necessary for health planners and care providers. A cross sectional study was conducted at El-Rahad hospital, Sudan to investigate seroprevalence of CMV and rubella infections and associated possible risk factors among pregnant women. Structured questionnaires were used to gather socio-demographic data and ELISA was used to detect CMV and rubella infections using IgG and IgM. Out of 231 pregnant women, 167 (72.2%) and 151 (65.3%) were CMV-IgG and rubella-IgG positive, respectively. Only 6 (2.5%) and 8 women (3.4%) were CMV-IgM and rubella-IgM positive, respectively. While, high parity (OR = 14.7, 95%CI = 1.7 - 123.6; P = 0.01] and illiteracy (OR = 3.0, CI = 1.4 - 6.5; P = 0.004) were significantly associated with seropostive CMV-IgG in multivariate analysis, none of the other obstetrical and medical characteristics were significantly associated with CMV or rubella infections. CMV prevalence was 72.2% and rubella susceptibility among pregnant women was 34.6%. Rubella vaccine and routine screening for rubella and CMV should be introduced for pregnant women in this setting. Further research is needed.


Akt activation by estrogen in estrogen receptor-negative breast cancer cells.
It has been a common belief that estrogen regulates cellular responses through binding to its receptor, the estrogen receptor (ER). In the nucleus, estrogen modulates the expression of estrogen-responsive genes through the action of the ER at the transcriptional level. In the cytoplasm, the ER-dependent signaling pathway has been shown to be involved in the activation of Akt and the downstream molecules. It is not clear, however, whether estrogen can modulate cytoplasmic signaling in an ER-independent manner. Human breast cancer cell lines without detectable ERs such as MDA-MB-435 and MDA-MB-231 were treated in estrogen-depleted medium followed by a brief treatment with estrogen. The activation of Akt was evaluated by a phosphoserine antibody. Our results showed that estrogen stimulated Akt activation, as indicated by phosphorylation at Ser(473) of the oncoprotein, in ER-negative breast cancer cells. Activation of Akt by estrogen in these cells was time and dose dependent and could be blocked by inhibitors of phosphatidylinositol 3'-kinase and Src kinase but not by estrogen antagonists. Our results provide evidence as well as the mechanism of the receptor-independent function of estrogen, in which the antiapoptotic factor Akt is activated.


Atmospheric deposition and exceedances of critical loads from 1800-2025 for the conterminous United States.
Atmospheric deposition of nitrogen (N) and sulfur (S) has increased dramatically over pre-industrial levels, with many potential impacts on terrestrial and aquatic ecosystems. Quantitative thresholds, termed "critical loads" (CLs), have been developed to estimate the deposition rate above which damage is thought to occur. However, there remains no comprehensive comparison of when, where, and over what time periods individual CLs have been exceeded. We addressed this knowledge gap by combining several published data sources for historical and contemporary deposition, and overlaying these on six CL types from the National Critical Loads Database (NCLDv2.5; terrestrial acidification, aquatic acidification, lichen, nitrate leaching, plant community composition, and forest-tree health) to examine exceedances from 1800 to 2011. We expressed CLs as the minimum, 10th, and 50th percentiles within 12-km grid cells. Minimum CLs were relatively uniform across the country (200-400 eq·ha-1 ·yr-1 ), and have been exceeded for decades beginning in the early 20th century. The area exceeding minimum CLs peaked in the 1970s and 1980s, exposing 300,000 to 3 million km2 (depending on the CL type) to harmful levels of deposition, with a total area exceeded of 5.8 million km2 (~70% of the conterminous United States). Since then, deposition levels have dropped, especially for S, with modest reductions in exceedance by 2011 for all CL types, totaling 5.2 million km2 in exceedance. The 10th and 50th percentile CLs followed similar trends, but were not consistently available at the 12-km grid scale. We also examined near-term future deposition and exceedances in 2025 under current air quality regulations, and under various scenarios of climate change and additional nitrogen management controls. Current regulations were projected to reduce exceedances of any CL from 5.2 million km2 in 2011 to 4.8 million km2 in 2025. None of the additional N management or climate scenarios significantly affected areal exceedances, although exceedance severity declined. In total, it is clear that many CLs have been exceeded for decades, and are likely to remain so in the short term under current policies. Additionally, we suggest many areas for improvement to enhance our understanding of deposition and its effects to support informed decision making.


Residents' end-of-life decision making with adult hospitalized patients: a review of the literature.
The authors performed a structured literature review to understand residents' experiences with end-of-life (EOL) decision making with adult hospitalized patients, specifically regarding decisions to withhold or withdraw advanced life-support measures. An Ovid-based strategy was used to search Medline, ERIC, PsychINFO, and CINHAL databases for articles published between 1966 and February 2005, combining the domains of "resuscitation orders," "decision making," and "internship and residency." All quantitative and qualitative studies examining residents' EOL decision making with adult hospitalized patients were included. The authors developed and applied a scoring system for relevance and quality, performed data abstraction and quality assessment independently and in duplicate, then met to collate findings and identify factors in residents' EOL decision making. The searches yielded 884 articles, of which 26 were included. Variable methodologies precluded meta-analysis. In these studies, residents felt unprepared to handle patient EOL decision making, although exposure to EOL discussions helped them gain confidence. Residents' attitudes, skills, and knowledge were key determinants of whether EOL decisions were addressed. Many misinterpreted the terms "DNR" and "futility." Residents' understanding of the patient EOL decision-making process could be extremely variable, and their do-not-resuscitate discussions suboptimal. Residents' lived practice experience of the patient EOL decision-making process was often at odds with what they were taught in formal curricula. Educational strategies aimed at changing residents' knowledge, skills and attitude should address the hidden curriculum for the patient EOL decision-making process that is part of the experienced culture of every day practice. Future studies of this experienced culture would inform specific educational interventions.


Are the skills of neurological assessment in need of resuscitation?
The aim of this paper is to outline the background to several recent papers which highlight deficiencies in acute neurological care—all of which highlight (to differing degrees) issues in relation to neurological assessment with some proposed solutions. Given that 10% of acute emergency admissions are for neurological conditions (up to 20% if stroke included), this should be of concern to all acute medical physicians.


Neurosyphilis in the mixed urban-rural community of the Netherlands.
Neurosyphilis is caused by dissemination into the central nervous system of Treponema pallidum. Although the incidence of syphilis in the Netherlands has declined since the mid-1980s, syphilis has re-emerged, mainly in the urban centres. It is not known whether this also holds true for neurosyphilis. The epidemiology of neurosyphilis in Dutch general hospitals in the period 1999-2010 was studied in a retrospective cohort study. Data from the Dutch sexually transmitted infection (STI) clinics were used to analyse the number of patients diagnosed with syphilis in this period. An incidence of neurosyphilis of 0.47 per 100 000 adults was calculated, corresponding with about 60 new cases per year. This incidence was higher in the western (urbanised) part of the Netherlands, as compared with the more rural areas (0.6 and 0.4, respectively). The number of patients diagnosed with syphilis in STI clinics increased from 150 to 700 cases in 2004 and decreased to 500 new cases in 2010. The sex ratio was in favour of men, yielding a percentage of 90% of the syphilis cases and of 75% of the neurosyphilitic cases. The incidence of neurosyphilis was highest in men aged 35-65 years, and in women aged 75 years and above. The most frequently reported clinical manifestation of neurosyphilis was tabes dorsalis. In this study, 15% of the patients were HIV seropositive. The incidence of neurosyphilis in a mixed urban-rural community such as the Netherlands is comparable to that in other European countries. Most patients are young, urban and men, and given the frequent atypical manifestations of the disease reintroduction of screening for neurosyphilis has to be considered.


Evaluating Approaches to Linking Evictions Records:: Assessing the Feasibility of Research with Integrated Data.
This study investigates different approaches to integrating evictions data with Medicaid and homeless shelter utilization records at the individual level for the state of Delaware. We especially focus on evaluating the feasibility of creating an integrated dataset focused on children and adolescents through different approaches to matching. We attempt to link existing statewide records on evictions, Medicaid, and shelter from 2017-2019. We first compare direct match and probabilistic match approaches to linking evictions and Medicaid records, and then incorporate shelter records. Finally, we consider a limited set of characteristics relevant to potential future public health research among children who experienced eviction, had a shelter stay, and were enrolled in Medicaid. Direct matching resulted in a lower match (14%) rate than probabilistic matching (22%) of eviction records to Medicaid data. Homeless shelter records had a high match rate to Medicaid records, even when using a direct match (75%). A sizeable subset of children (n=216) were linked across the three data sources, though this was from a small percentage of cases in the evictions data. Among this subset of children, most (71%) were enrolled in Medicaid in all three years considered by this study and Black children were greatly overrepresented (75%). Integrating evictions records with other health and human service data involves a number of challenges. Probabilistic matching yielded a considerably higher number of matches after manual review, resulting in a possible study sample of children who have experienced eviction, a homeless shelter stay, and were enrolled in Medicaid. Strategies to increase the match rate for eviction records through using records from other, more universal services may be necessary for investigations that require more comprehensive coverage of the population.


A visual evaluation of oral plaque removal utilizing an adjunct enzyme pre-rinse in orthodontic subjects.
To determine if an adjunct proteolytic pre-rinse along with contemporary methods of dental cleaning may more effectively remove visual plaque in subjects with fixed orthodontic appliances. Forty-three orthodontic subjects, ages 10 to 25, completed this single site, double-blind, crossover clinical trial. Subjects randomly received bromelain enzyme or a powdered-sugar placebo pre-rinse, followed by manual tooth brushing and use of a Waterpik. Subjects received the alternate pre-rinse during the subsequent visit. Baseline and residual plaque accumulation were recorded via disclosing tablet and digital photography. A single, blinded examiner scored visual plaque scores from randomized photographs. Treatment effects on composite plaque score were evaluated using repeated-measures analysis of variance. A 5% significance level was used for all tests. No significant differences in plaque scores were noted at baseline or post-rinse between the enzyme and placebo. The changes from baseline to post-rinse (P = .190), post-brushing (P = .764), and post-Waterpik (P = .882) were not significantly different between interventions. Significant reduction in plaque scores were observed in both arms of the study after brushing (P < .01) and waterjet use (P < .01). Neither age (P = .220) nor gender (P = .449) impacted plaque scores. Use of a bromelain enzyme pre-rinse alone did not significantly enhance plaque removal. A significant reduction in retained plaque was observed with the application of brushing and or Waterpik.


Relating quality of life to Glasgow outcome scale health states.
There has recently been a call for the adoption of comparative effectiveness research (CER) and related research approaches for studying traumatic brain injury (TBI). These methods allow researchers to compare the effectiveness of different therapies in producing patient-oriented outcomes of interest. Heretofore, the only measures by which to compare such therapies have been mortality and rate of poor outcome. Better comparisons can be made if parametric, preference-based quality-of-life (QOL) values are available for intermediate outcomes, such as those described by the Glasgow Outcome Scale Extended (GOSE). Our objective was therefore to determine QOL for the health states described by the GOSE. We interviewed community members at least 18 years of age using the standard gamble method to assess QOL for descriptions of GOSE scores of 2-7 derived from the structured interview. Linear regression analysis was also performed to assess the effect of age, gender, and years of education on QOL. One hundred and one participants between the ages of 18 and 83 were interviewed (mean age 40 ± 19 years), including 55 men and 46 women. Functional impairment and QOL showed a strong inverse relationship, as assessed by both linear regression and the Spearman rank order coefficient. No consistent effect or age, gender, or years of education was seen. As expected, QOL decreased with functional outcome as described by the GOSE. The results of this study will provide the groundwork for future groups seeking to apply CER methods to clinical studies of TBI.


Carriage rates of Neisseria meningitidis serogroups: determination among freshmen conscripts before vaccination.
Neisseria meningitidis is transmitted from person-to-person. Thus, close contact with a healthy carrier can facilitate the spread of the bacteria and lead to life-threatening meningococcal disease. The aim of this study was to identify oropharyngeal carriers of N. meningitidis in volunteers preparing for military service before vaccination. In a cross-sectional study, 226 volunteers entering military service were referred to the Shemiranat Health Center for meningococcal vaccination and assayed. Before vaccination, the participants underwent sampling of the throat using separate swabs. Thayer-Martin Agar medium and microbiological standard methods were used for culture and isolation of the organisms. The bacterial isolates were subjected to DNA extraction and polymerase chain reaction. The obtained data were descriptively analyzed. Out of the 226 (100%) young volunteers, only 18 (8%) yielded Gram-negative diplococci. The results showed the presence of N. meningitidis (carriage rate: 8%) in their oropharyngeal regions. The isolated serogroups were C, A, Y, W-135, and X with frequencies of 50, 22.2, 16.6, 5.5, and 5.5, respectively. This study showed that the carriage rate in young volunteers for military service is around 8% before vaccination. Although the rates for serogroups A and C were dominant, the existence of serogroups Y and W indicate the necessary revision of the A/C vaccine. More research is needed to determine serogroup diversity and decrease the risk of meningococcal disease in individual groups.


Acute long-distance trail running increases serum IL-6, IL-15, and Hsp72 levels.
Interleukin-6 (IL-6), IL-15, and heat shock protein 72 (Hsp72) are molecules that have significant metabolic effects on glucose and fat metabolism and a cell's stress response. The aim of this study is to determine serum levels of these molecules in runners after a long-distance trail run. Serum IL-15 levels after such endurance events have not been investigated yet. Blood samples were collected from 37 athletes (11 female, 26 male) before and after a 35-km trail run, with a total climb of 940 m. Serum was obtained from the samples, and IL-6, IL-15, and Hsp72 levels were measured from using the sandwich ELISA method. The athletes completed the race in 308.3 ± 37.4 min on average. After the race, the mean serum IL-6, IL-15, and Hsp72 concentrations increased 13.2-fold, 2.22-fold, and 1.6-fold, respectively (p < 0.001, p < 0.001, and p = 0.039, respectively). This is the first study to demonstrate the increase in serum IL-15 levels following an acute endurance exercise. In addition to IL-15, we report that IL-6 and soluble Hsp72 levels also increased significantly following a 35-km trail run. Since these molecules are involved in regulating glucose and fat metabolism, significant increases of IL-6, IL-15, and soluble Hsp72 may have health benefits that may be associated with long-distance trail runs, which are becoming more popular worldwide.


From big data to rich data: The key features of athlete wheelchair mobility performance.
Quantitative assessment of an athlete׳s individual wheelchair mobility performance is one prerequisite needed to evaluate game performance, improve wheelchair settings and optimize training routines. Inertial Measurement Unit (IMU) based methods can be used to perform such quantitative assessment, providing a large number of kinematic data. The goal of this research was to reduce that large amount of data to a set of key features best describing wheelchair mobility performance in match play and present them in meaningful way for both scientists and athletes. To test the discriminative power, wheelchair mobility characteristics of athletes with different performance levels were compared. The wheelchair kinematics of 29 (inter-)national level athletes were measured during a match using three inertial sensors mounted on the wheelchair. Principal component analysis was used to reduce 22 kinematic outcomes to a set of six outcomes regarding linear and rotational movement; speed and acceleration; average and best performance. In addition, it was explored whether groups of athletes with known performance differences based on their impairment classification also differed with respect to these key outcomes using univariate general linear models. For all six key outcomes classification showed to be a significant factor (p<0.05). We composed a set of six key kinematic outcomes that accurately describe wheelchair mobility performance in match play. The key kinematic outcomes were displayed in an easy to interpret way, usable for athletes, coaches and scientists. This standardized representation enables comparison of different wheelchair sports regarding wheelchair mobility, but also evaluation at the level of an individual athlete. By this means, the tool could enhance further development of wheelchair sports in general.


[Receptor-ligand docking simulation for membrane proteins].
Protein structure-based molecular design using the computational techniques of protein structure prediction, ligand docking, and virtual screening is an integral part of drug discovery for limiting the application of the structure-based approach to target proteins such as G-protein-coupled receptors (GPCRs). GPCRs play an important role in living organisms and are of major interest to the pharmaceutical industry. However, structural data on ligand-binding forms for GPCRs from experiments to elucidate structural templates for docking simulations are lacking due to the difficulties associated with crystallization and crystallography. Therefore structural prediction of GPCRs in the ligand-bound state using computational methods has been introduced, but the prediction of ligand conformation onto target GPCRs is still constructed manually by human experts. We developed a molecular modeling technique for the prediction of ligand-receptor binding using comparative ligand-binding analysis (CoLBA) that not only considers interaction energy but also the similarity of interaction profiles among ligands. The advantage of CoLBA is that it can facilitate intuitive and flexible screening based on docking results when protein structures with low resolution (or theoretical models) are targeted. We applied CoLBA to ligand-binding prediction in several GPCRs. The predicted ligand-binding models were evaluated in site-directed mutagenesis experiments in collaborative research, and the enrichment rate of activated ligands was compared with random compounds in virtual screening simulations. We propose that CoLBA can be applied in large-scale modeling of ligand-receptor complexes and virtual screening for GPCRs.


Persistent and recurrent disease in patients with papillary thyroid carcinoma with clinically apparent (cN1), but not extensive, lymph node involvement and without other factors for poor prognosis.
Lymph node metastases (LNM) are frequent in patients with papillary thyroid cancer (PTC). The risk of persistent disease (PD) and tumor recurrence (TR) is increased when factors for poor prognosis other than LNM exist, when LNM are numerous, large, detected by preoperative ultrasonography (US), or exhibit extranodal extension. This study evaluated the risk of PD and TR in patients with LNM not exhibiting these characteristics. Eighty-six patients with 5 or fewer LNM detected during intraoperative inspection, but not by preoperative US, who had no other factors for poor prognosis [tumors > 4 cm, extensive extrathyroid invasion, vascular invasion, aggressive histological subtype, distant metastases, incomplete tumor resection], were studied. All patients underwent total thyroidectomy followed by radioiodine ablation. PD was defined as metastases on initial post-therapy whole-body scans (RxWBS) or detected by imaging methods up to 12 months after ablation. TR was defined as structural disease diagnosed more than one year after ablation in patients without PD. PD was diagnosed in 3/86 patients (3.5%). TR was observed in 2/83 patients (2.5%) after 62 months of follow-up. There was no case of death due to the disease. A correlation was observed between pre-ablation Tg and PD or TR [1/48 (2%) with Tg ≤ 2 ng/mL versus 2/22 (9%) with Tg > 2 ≤ 10 ng/mL versus 2/7 (28.5%) with Tg ≥ 10 ng/ml)]. It is noteworthy that 38 patients had up to 3 positive LN and pre-ablation Tg ≤ 2 ng/ml, and none of them had PD or TR. The frequency of PD and TR was low in patients with PTC with 5 or fewer LNM and without other factors for poor prognosis. Low postoperative stimulated Tg was predictive of the absence of PD and TR in these patients.


Characteristics and allowed behaviors of gay male couples' sexual agreements.
Research has shown that gay male couples' sexual agreements may affect their risk for HIV. Few U.S. studies have collected dyadic data nationally from gay male couples to assess what sexual behaviors they allow to occur by agreement type and the sequence of when certain behaviors occur within their relationships. In our cross-sectional study, dyadic data from a convenience sample of 361 male couples were collected electronically throughout the United States by using paid Facebook ads. Findings revealed that couples discussed their HIV status before having unprotected anal intercourse (UAI) but established their agreement some time after having UAI. About half of the couples (N = 207) concurred about having an agreement. Among these couples, 58% concurred about explicitly discussing their agreement, 84% concurred about having the same type of agreement, and 54% had both men adhering to it. A variety of sexual behaviors were endorsed and varied by agreement type. Concordance about aspects of couples' agreements varied, suggesting the need to engage couples to be more explicit and detailed when establishing and communicating about their agreements. The allowed behaviors and primary reasons for establishing and breaking sexual agreements further highlight the need to bolster HIV prevention for gay male couples.


SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19.
Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear. Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients. We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl3-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo. We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count. Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients. Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming. SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo. Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation. SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte-platelet aggregates. Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation. Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2. SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients.


Spectrum of antihypertensive therapy in South Asians at a tertiary care hospital in Pakistan.
Despite available guidelines on hypertension (HTN), use of antihypertensives is variable. This study was designed to ascertain frequency of patients on monotherapy and > 1 antihypertensive therapy and also to ascertain proportion of patients on diuretic therapy. It was a crossectional study conducted on 1191 adults(age > 18 yrs)hypertensive patients selected by computerized International Classification of Diseases -9-coordination and maintenance (ICD-9-CM) presenting to a tertiary care hospital in Pakistan. Data on demographics, comorbids, type of antihypertensive drug, number of antihypertensive drug and mean duration of antihypertensive drug was recorded over 1.5 year period (2008-09). Blood pressure was recorded on admission. Primary outcome was use of combination therapy and secondary outcome was use of diuretic therapy. A total of 1191 participants were included. Mean age(SD) was 62.55(12.47) years, 45.3%(540) were males. Diabetes was the most common comorbid; 46.3%(551). Approximately 85% of patients had controlled hypertension. On categorization of anti hypertensive use into 3 categories;41.2%(491) were on monotherapy,32.2%(384) were on 2 drug therapy,26.5%(316) were on ≥3 drug therapy. Among those who were on monotherapy for HTN;34%(167) were on calcium channel blockers,30.10%(148) were on beta blockers, 22.80%(112) were on Angiotensin converting enzyme (ACE) inhibitors,12%(59) were on diuretics and 2.20%(11) were on Angiotensin receptor blockers(ARB). Use of combination antihypertensive therapy was significantly high in patients with ischemic heart disease(IHD)(p < 0.001). Use of diuretics was in 31% (369) patients. Use of diuretics was significantly less in patients with comorbids of diabetes (p 0.02), Chronic kidney disease(CKD)(p 0.003), IHD (p 0.001) respectively Most patients presenting to our tertiary care center were on combination therapy. Calcium channel blocker is the most common anti hypertensive drug used as monotherapy and betablockers are used as the most common antihypertensive in combination. Only a third of patients were on diuretic as an antihypertensive therapy.


Trabeculectomy With Mitomycin-C: Outcomes and Risk Factors for Failure in Primary Angle-closure Glaucoma.
There are no reported large series of trabeculectomy with mitomycin-C (MMC) in Western patients with primary angle-closure glaucoma (PACG). Our study evaluates long-term tonometric outcomes of trabeculectomy in PACG. This is a retrospective cohort study. The primary outcomes were the Kaplan-Meier success rates on survival analyses using 3 criteria, with or without adjunctive medication: (A) intraocular pressure (IOP) ≤18 mm Hg and IOP reduction of 20%; (B) IOP≤15 mm Hg and IOP reduction 25%; and (C) IOP≤12 mm Hg and IOP reduction 30%. In total, 136 eyes (102 patients) with PACG who underwent trabeculectomy MMC were included. The Cox proportional hazard regression analysis was used to identify risk factors for failure with multivariate analysis (P<0.05). The qualified success rates (±SD) after 1, 3, and 5 years of follow-up for criterion A were 92% (±2.2%), 78% (±3.8%), and 72% (±4.3%); for criterion B, 86% (±3.0%), 65% (±4.4%), and 59% (±4.7%); and for criterion C, 62% (±4.2%), 40% (±4.5%), and 32% (±4.4%). Baseline factors associated with failure were: family history, absence of laser peripheral iridotomy, higher IOP, and presence of a crystalline lens. Trabeculectomy with MMC effectively reduces IOP in PACG. Long-term IOP reduction is achieved for target IOP levels in the mid-teens. Presence of a crystalline lens, lack of iridotomy and higher preoperative IOP were associated with higher risks of failure.


Acute Dialysis Quality Initiative II: the Vicenza conference.
The process of tackling all of the issues related to acute renal failure began with the initial focus on its dialytic management (Acute Dialysis Quality Initiative I: the New York conference), because this required urgent attention. However, it was clear from the start that the entire issue of acute renal failure, including its definition, epidemiology inside and outside of the intensive care unit, the animal models used to develop new interventions, the issue of fluid therapy, the application of information technology to its care, the choice of appropriate physiologic goals for phase I and phase II studies, and the need to define appropriate clinical goals for large, randomized, clinical trials, required systematic attention. Accordingly, the second Acute Dialysis Quality Initiative conference in Vicenza, Italy, was organized, and its goals and rationale are presented in this report.


Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue.
Estracyt (EMP) has been used for the treatment of hormone refractory prostate cancer for many years. Recently, new data from combination studies have given rise to new interest in this old drug. Explanations for the synergy found in the clinic are many, but one major factor may be the previous indication that the drug accumulates in the prostate tumor. We have, therefore, examined the level of the four metabolites, estromustine (EoM), estramustine (EaM), estrone, and estradiol in the tumor and serum of 14 patients with T2 and T3 prostate cancer receiving a single i.v. dose of 600 mg of EMP, about 12 h before radical prostatectomy. Because it has been suggested that the uptake into the prostate tumor is due to binding to the estramustine binding protein (EMBP), we have in addition measured the level of EMBP in the prostate tumor tissue. The main serum and tissue metabolite in all patients was EoM followed by EaM, estrone, and estradiol. The levels for EoM ranged from 63.8-162.8 ng/ml in the serum and from 64.8-1209 ng/ml in the prostate tumor, resulting in a mean ratio for serum to tumor of 1:5. The levels for EaM ranged from 8.3-51.4 ng/ml in the serum and 73.9-563.4 ng/ml in the tumor, giving a mean ratio for serum to tumor of 1:13. The levels of EMBP were higher in T3 tumors than in T2 tumors, 54.1 and 40.7 ng/g tissue, respectively. A significant correlation was found between the levels of EaM (r = 0.60) and the levels of EMBP in the tumor. These data demonstrate that 12 h after a single i.v. dose of 600 mg of EMP the levels of the cytotoxic metabolites EoM and EaM are substantially higher in the tumor than in the serum of the same patient and that a correlation exists between the levels of EaM in the tumor and the levels of EMBP. Thus, this supports the hypothesis that the EMBP is responsible for the retention of EoM and EaM in the prostate tumor.


The effect of bedrails on falls and injury: a systematic review of clinical studies.
around one-fourth of all falls in healthcare settings are falls from bed. The role of bedrails in falls prevention is controversial, with a prevailing orthodoxy that bedrails are harmful and ineffective. to summarise and critically evaluate evidence on the effect of bedrails on falls and injury systematic literature review using the principles of QuoRoM guidance. adult healthcare settings using the keyword, bedrail, and synonyms, databases were searched from 1980 to June 2007 for direct injury from bedrails or where falls, injury from falls, or any other effects were related to bedrail use. 472 papers were located; 24 met the criteria. Three bedrail reduction studies identified significant increases in falls or multiple falls, and one found that despite a significant decrease in falls in the discontinue-bedrails group, this group remained significantly more likely to fall than the continue-bedrails group; one case-control study found patients who had their bedrails raised significantly less likely to fall; one retrospective survey identified a significantly lower rate of injury and head injury in falls with bedrails up. Twelve papers described direct injury from bedrails. it is difficult to perform conventional clinical trials of an intervention already embedded in practice, and all included studies had methodological limitations. However, this review concludes that serious direct injury from bedrails is usually related to use of outmoded designs and incorrect assembly rather than being inherent, and bedrails do not appear to increase the risk of falls or injury from falls.


Conformal prostate treatment planning using a low-energy (6-MV) beam.
A 4-field noncoplanar technique for treatment of prostate cancer developed at the University of Michigan was modified for use with low-energy (6 MV) beams. These modifications include the use of wedges on the 2 anterior inferior-superior oblique fields and adjusting the weights of the oblique and lateral fields appropriately. A margin of 1.5 cm around the physician-defined target region was used to define the blocks on each beam's-eye view. Dose distributions produced using this technique with 6-MV and 24-MV beams were compared visually on several dose planes (transverse and sagittal) and quantitatively by dose volume histograms (target, rectum, and bladder). These comparisons showed insignificant differences between the high-energy and low-energy treatment plans. Much larger differences were observed in comparisons of 2 types of coplanar plans with the noncoplanar setup for the 6-MV photon machine. Rectal doses measured in situ were used to help validate the dose distribution predicted by the treatment planning system for the 6-MV noncoplanar technique.


Development of linear and nonlinear predictive QSAR models and their external validation using molecular similarity principle for anti-HIV indolyl aryl sulfones.
Quantitative structure-activity relationship (QSAR) studies have been carried out on indolyl aryl sulfones, a class of novel HIV-1 non-nucleoside reverse transcriptase inhibitors, using physicochemical, topological and structural parameters along with appropriate indicator variables. The statistical tools used were linear methods (e.g., stepwise regression analysis, partial least squares (PLS), factor analysis followed by multiple regression (FA-MLR), genetic function approximation combined with multiple linear regression (GFA-MLR) and GFA followed by PLS or G/PLS and nonlinear method (artificial neural network or ANN). In case of physicochemical parameters, GFA-MLR generated the best Equation (n = 97, R(2) = 0.862, Q(2) = 0.821). Using topological parameters, the best Equation (based on leave-one-out Q(2)) was obtained with stepwise regression technique (n = 97, R(2) = 0.867, Q(2) = 0.811). When topological and physicochemical parameters were used in combination, statistical quality increased to a great extent (n = 97, R(2) = 0.891, Q(2) = 0.849 from stepwise regression). Furthermore, the whole dataset had been divided into test (25% of whole dataset) and training (remaining 75%) sets. Models were developed based on the training set and predictive potential of such models was checked from the test set. The selection of the training set was based on K-means clustering of the standardized descriptors (topological and physicochemical). In this case also the best results were obtained with stepwise regression (n = 72, R(2) = 0.906, Q(2) = 0.853) but external predictive capacity of this model ([image omitted] ) was inferior to the model developed from GFA-MLR technique (R(2) = 0.883, Q(2) = 0.823, [image omitted] ). However, the squared regression coefficient between observed activity and predicted activity values of the test set compounds for the best linear model, i.e., GFA-MLR (r(2) = 0.736) was lower in comparison to the best nonlinear model developed using artificial neural network (r(2) = 0.781). Thus, based on external validation, the ANN models were superior to the linear models. The predictive potential of the best linear Equation (stepwise regression model) was superior to that of the previously published CoMFA (Q(2) = 0.81, SDEP(Test) = 0.89) on the same data set (Ragno R. et al., J Med Chem 2006, 49, 3172-3184). Furthermore, the physicochemical parameter based models also supported the previous observations based on docking (Ragno R. et al., J Med Chem 2005, 48, 213-223).


Perspectives on artificial intelligence programming.
Programs are judged not only by whether they faithfully carry out the intended processing but also by whether they are understandable and easily changed. Programming systems for artificial intelligence applications use specialized languages, environments, and knowledge-based tools to reduce the complexity of the programming task. Language styles based on procedures, objects, logic, rules, and constraints reflect different models for organizing programs and facilitate program evolution and understandability. To make programming easier, multiple styles can be integrated as sublanguages in a programming environment. Programming environments provide tools that analyze programs and create informative displays of their structure. Programs can be modified by direct interaction with these displays. These tools and languages are helping computer scientists to regain a sense of control over systems that have become increasingly complex.


Superoxide and the production of oxidative DNA damage.
The conventional model of oxidative DNA damage posits a role for superoxide (O2-) as a reductant for iron, which subsequently generates a hydroxyl radical by transferring the electron to H2O2. The hydroxyl radical then attacks DNA. Indeed, mutants of Escherichia coli that lack superoxide dismutase (SOD) were 10-fold more vulnerable to DNA oxidation by H2O2 than were wild-type cells. Even the pace of DNA damage by endogenous oxidants was great enough that the SOD mutants could not tolerate air if enzymes that repair oxidative DNA lesions were inactive. However, DNA oxidation proceeds in SOD-proficient cells without the involvement of O2-, as evidenced by the failure of SOD overproduction or anaerobiosis to suppress damage by H2O2. Furthermore, the mechanism by which excess O2- causes damage was called into question when the hypersensitivity of SOD mutants to DNA damage persisted for at least 20 min after O2- had been dispelled through the imposition of anaerobiosis. That behavior contradicted the standard model, which requires that O2- be present to rereduce cellular iron during the period of exposure to H2O2. Evidently, DNA oxidation is driven by a reductant other than O2-, which leaves the mechanism of damage promotion by O2- unsettled. One possibility is that, through its well-established ability to leach iron from iron-sulfur clusters, O2- increases the amount of free iron that is available to catalyze hydroxyl radical production. Experiments with iron transport mutants confirmed that increases in free-iron concentration have the effect of accelerating DNA oxidation. Thus, O2- may be genotoxic only in doses that exceed those found in SOD-proficient cells, and in those limited circumstances it may promote DNA damage by increasing the amount of DNA-bound iron.


Shear stress-induced [Ca2+]i transients and oscillations in mouse fibroblasts are mediated by endogenously released ATP.
The effects of ATP, U-73122, apyrase, and saline shear stress on [Ca2+]i homeostasis were studied in fura-2 loaded, mouse fibroblast cells (L929), both in suspension and plated on glass. Release of internal Ca2+ was induced by ATP, via a receptor identified pharmacologically as a P2U type. In single cells, low concentrations of ATP evoked [Ca2+]i oscillations. These events were blocked by the putative phospholipase C inhibitor, U-73122 (but not by the inactive analog U-73343) and by the ATP/ADPase, apyrase. In addition, both these agents reduced the [Ca2+]i of unstimulated cells, especially after stirring, and blocked spontaneously occurring [Ca2+]i oscillations, which suggested an already activated state of the ATP receptor, independent from exogenous stimulations. Moreover, it was found that stirring of the cells was correlated with a steady accumulation of inositol phosphates, also blockable by apyrase, and that [Ca2+]i mobilization could be induced by puffs of saline in single cells. The transition to a Ca(2+)-free environment also provoked [Ca2+]i oscillations, most likely via the increase in ATP4- concentration. This evidence suggests that endogenous ATP is released from L fibroblasts in response to fluid shear stress, and this results in an autocrine, tonic up-regulation of the phosphoinositide signaling system and an ensuing alteration in Ca2+ homeostasis. Up until now, such a response to shear stress was believed to be unique to endothelial cells.


A comparison of Rasch item-fit and Cronbach's alpha item reduction analysis for the development of a Quality of Life scale for children and adolescents.
This study compares item reduction analysis based on classical test theory (maximizing Cronbach's alpha - approach A), with analysis based on the Rasch Partial Credit Model item-fit (approach B), as applied to children and adolescents' health-related quality of life (HRQoL) items. The reliability and structural, cross-cultural and known-group validity of the measures were examined. Within the European KIDSCREEN project, 3019 children and adolescents (8-18 years) from seven European countries answered 19 HRQoL items of the Physical Well-being dimension of a preliminary KIDSCREEN instrument. The Cronbach's alpha and corrected item total correlation (approach A) were compared with infit mean squares and the Q-index item-fit derived according to a partial credit model (approach B). Cross-cultural differential item functioning (DIF ordinal logistic regression approach), structural validity (confirmatory factor analysis and residual correlation) and relative validity (RV) for socio-demographic and health-related factors were calculated for approaches (A) and (B). Approach (A) led to the retention of 13 items, compared with 11 items with approach (B). The item overlap was 69% for (A) and 78% for (B). The correlation coefficient of the summated ratings was 0.93. The Cronbach's alpha was similar for both versions [0.86 (A); 0.85 (B)]. Both approaches selected some items that are not strictly unidimensional and items displaying DIF. RV ratios favoured (A) with regard to socio-demographic aspects. Approach (B) was superior in RV with regard to health-related aspects. Both types of item reduction analysis should be accompanied by additional analyses. Neither of the two approaches was universally superior with regard to cultural, structural and known-group validity. However, the results support the usability of the Rasch method for developing new HRQoL measures for children and adolescents.


Severe hemoptysis in post-tuberculosis bronchiectasis precipitated by SARS-CoV-2 infection.
Since the beginning of SARS-CoV-2 outbreak in China, severe acute respiratory syndrome has been widely descripted. Hemoptysis has rarely been observed in SARS-CoV-2 infection. We report here a case of severe hemoptysis in post-tuberculosis bronchiectasis precipitated by SARS-CoV-2 infection and managed in a referral center. A 58-year-old man was admitted to our intensive care unit for severe hemoptysis with history of post-tuberculosis bronchiectasis. At ICU admission the patient had fever and severe acute respiratory failure requiring high flow oxygen therapy. Respiratory tract sampling was positive for SARS-CoV-2. Multi-detector computed tomography angiography pointed out localized bronchiectasis on the left lower lobe and enlarged left bronchial and phrenic arteries; bronchial arteriography with distal embolization was performed with favorable outcome and no bleeding recurrence. To our knowledge, this is the first case of acute exacerbation of bronchiectasis related to SARS-CoV-2 infection and complicated by severe hemoptysis. Whether the virus may play a role in the dysregulation of airway haemostasis, and contribute to episodes of hemoptysis in patients with chronic pulmonary diseases and predisposing factors might be investigated.


Impacts of Whole-Body Vibration on Muscle Strength, Power, and Endurance in Older Adults: A Systematic Review and Meta-Analysis.
Randomized clinical trials (RCTs) were conducted to identify the effectiveness of whole-body vibration (WBV) on strength, power, and muscular endurance in older adults. However, the results of different studies are contradictory. To verify the impacts of the WBV on strength, power, and muscular endurance in older adults. The search was carried out in PubMed, Embase, CENTRAL, CINAHL, SPORTDiscus, Web of Science, LILACS and PEDro databases. Methodological quality was assessed using the PEdro scale. Meta-analysis calculations were performed using the standardized mean difference, comparing WBV with control groups and WBV with other types of exercise. Thirty-four studies were included in the current systematic review. Most studies (56%) had low methodological quality (PEDro score < 6). WBV, compared with control groups, has significant effects on muscle strength of knee extensors and flexors, lower limb extensors, and ankle plantar flexors. There were no differences between WBV and other types of exercise. Subgroup analyzes demonstrated that, in general, the significant results observed in the primary analyzes were not dependent on body position during vibration, kind of vibration, cumulative dose or magnitude of WBV. WBV was effective in increasing lower limb muscle strength. However, no significant results were observed for upper limb strength, lower limb power, and lower and upper limb muscle endurance in older adults. However, more studies are needed to better understand the physiological impacts of WBV in older.


Integrated use of bioinformatic resources reveals that co-targeting of histone deacetylases, IKBK and SRC inhibits epithelial-mesenchymal transition in cancer.
With the advent of high-throughput technologies leading to big data generation, increasing number of gene signatures are being published to predict various features of diseases such as prognosis and patient survival. However, to use these signatures for identifying therapeutic targets, use of additional bioinformatic tools is indispensible part of research. Here, we have generated a pipeline comprised of nearly 15 bioinformatic tools and enrichment statistical methods to propose and validate a drug combination strategy from already approved drugs and present our approach using published pan-cancer epithelial-mesenchymal transition (EMT) signatures as a case study. We observed that histone deacetylases were critical targets to tune expression of multiple epithelial versus mesenchymal genes. Moreover, SRC and IKBK were the principal intracellular kinases regulating multiple signaling pathways. To confirm the anti-EMT efficacy of the proposed target combination in silico, we validated expression of targets in mesenchymal versus epithelial subtypes of ovarian cancer. Additionally, we inhibited the pinpointed proteins in vitro using an invasive lung cancer cell line. We found that whereas low-dose mono-therapy failed to limit cell dispersion from collagen spheroids in a microfluidic device as a metric of EMT, the combination fully inhibited dissociation and invasion of cancer cells toward cocultured endothelial cells. Given the approval status and safety profiles of the suggested drugs, the proposed combination set can be considered in clinical trials.


Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.
Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.


Metabolic phenotypes of obesity: frequency, correlates and change over time in a cohort of postmenopausal women.
The possibility that a subset of persons who are obese may be metabolically healthy-referred to as the 'metabolically healthy obese' (MHO) phenotype-has attracted attention recently. However, few studies have followed individuals with MHO or other obesity phenotypes over time to assess change in their metabolic profiles. The aim of the present study was to examine transitions over a 6-year period among different states defined simultaneously by body mass index (BMI) and the presence/absence of the metabolic syndrome (MetS). We used repeated measurements available for a subcohort of participants enrolled in the Women's Health Initiative (N=3512) and followed for an average of 6 years to examine the frequency of different metabolic obesity phenotypes at baseline, the 6-year transition probabilities to other states and predictors of the risk of different transitions. Six phenotypes were defined by cross-tabulating BMI (18.5-<25.0, 25.0-<30.0, ⩾30.0 kg m-2) by MetS (yes, no). A continuous-time Markov model was used to estimate 6-year transition probabilities from one state to another. Over the 6 years of follow-up, one-third of women with the healthy obese phenotype transitioned to the metabolically unhealthy obese (MUO) phenotype. Overall, there was a marked tendency toward increased metabolic deterioration with increasing BMI and toward metabolic improvement with lower BMI. Among MHO women, the 6-year probability of becoming MUO was 34%, whereas among unhealthy normal-weight women, the probability of 'regressing' to the metabolically healthy normal-weight phenotype was 52%. The present study demonstrated substantial change in metabolic obesity phenotypes over a 6-year period. There was a marked tendency toward metabolic deterioration with greater BMI and toward metabolic improvement with lower BMI.


Childhood precursors of age at first intercourse for females.
Age at first intercourse for a sample of adult white women using variables measured during childhood is predicted. Childhood predictors were measured at birth, and ages 5 and 9-11, using existing public-use data on the women. Median age at first intercourse for the sample was 17.5 years. Early family predictors, early developmental characteristics, and temperamental characteristics during childhood together could predict about a fourth of the variance in age at first intercourse. The strongest predictors were motor skills and nightmares at age 5, church attendance with family at age 9, and domineering and mature personality at age 9.


Microbial Community Interactions Are Sensitive to Small Changes in Temperature.
Microbial communities are essential for human and environmental health, often forming complex interaction networks responsible for driving ecosystem processes affecting their local environment and their hosts. Disturbances of these communities can lead to loss of interactions and thereby important ecosystem functionality. The research on what drives interactions in microbial communities is still in its infancy, and much information has been gained from the study of model communities. One purpose of using these model microbial communities is that they can be cultured under controlled conditions. Yet, it is not well known how fluctuations of abiotic factors such as temperature affect their interaction networks. In this work, we have studied the effect of temperature on interactions between the members of the model community THOR, which consists of three bacterial species: Pseudomonas koreensis, Flavobacterium johnsoniae, and Bacillus cereus. Our results show that the community-intrinsic properties resulting from their interspecies interactions are highly dependent on incubation temperature. We also found that THOR biofilms had remarkably different abundances of their members when grown at 11, 18, and 25°C. The results suggest that the sensitivity of community interactions to changes in temperature is influenced, but not completely dictated, by different growth rates of the individual members at different temperatures. Our findings likely extend to other microbial communities and environmental parameters. Thus, temperature could affect community stability and may influence diverse processes including soil productivity, bioprocessing, and disease suppression. Moreover, to establish reproducibility between laboratories working with microbial model communities, it is crucial to ensure experimental stability, including carefully managed temperature conditions.


Quantifying vascular density and morphology using different swept-source optical coherence tomography angiographic scan patterns in diabetic retinopathy.
To evaluate quantitative metrics of the retinal microvasculature in eyes with diabetic retinopathy (DR) using various en face swept-source optical coherence tomography angiography (SS-OCTA) image sizes. Non-segmented and segmented images were acquired using an SS-OCTA device (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, California, USA). The scanning protocols included the 3×3 mm, 6×6 mm and 12×12 mm fields of view. Quantitative analysis of the perfusion density (PD), vessel length density (VLD) and fractal dimension (FD) was performed. The area under the receiver operating characteristic curve was estimated to assess the ability of each image size to predict DR. This prospective, cross-sectional study included 60 eyes, (non-DR, 13 eyes; non-proliferative DR (NPDR), 24 eyes; proliferative DR (PDR), 23 eyes) of 46 patients with diabetes and 21 eyes of 16 healthy individuals. In the 12×12 mm images, the PD of healthy individuals was significantly greater than that of patients with NPDR or PDR for all layers (NPDR, p<0.05; PDR, p<0.001 0.001; FD, p<0.001) or PDR (VLD, p<0.001; FD, p<0.001 for all layers). The results were similar for the 3×3 mm and 6×6 mm images. Overall, PD, VLD and FD progressively decreased with worsening DR severity in segmented and non-segmented layers for all SS-OCTA scan sizes. For detecting DR, 3×3 mm images best predicted DR for all evaluated quantitative parameters. Vascular changes in DR can be monitored in detail through quantitative evaluations that combine different SS-OCTA scan sizes and parameters.


An iridovirus from larvae of Culiseta annulata and Culex territans.
Field-collected 4th instar larvae of Culiseta annulata and Culex territans were found to be infected with mosquito iridescent virus (MIV). Ultrathin sections revealed the presence in infected cells of different types of immature virus particles of an average diameter of 180 and 190 nm respectively.


Whole grains: benefits and challenges.
Inclusion of whole grains (WG) in the diet is recommended in dietary guidance around the world because of their associations with increased health and reduced risk of chronic disease. WGs are linked to reduced risk of obesity or weight gain; reduced risk of cardiovascular disease (CVD), including coronary heart disease (CHD), hypertension, and stroke; improved gut health and decreased risk of cancers of the upper gut; perhaps reduced risk of colorectal cancer; and lower mortality rate. The 2005 United States Dietary Guidelines Advisory Committee has recommended that consumers make "half their grains whole." Yet, whole grains are puzzling both consumers and scientists. Scientists are trying to determine whether their health benefits are due to the synergy of WG components, individual WG components, or the fact that WG eaters make many of the recommended diet and lifestyle choices. Consumers need to understand the WG benefits and how to identify WG foods to have incentive to purchase and use such foods. Industry needs to develop great-tasting, clearly-labeled products. With both these factors working together, it will be possible to change WG consumption habits among consumers.


Cytotoxic T lymphocytes recognize and lyse chondrocytes under inflammatory, but not non-inflammatory conditions.
The human major histocompatibility complex (MHC) class I allele HLA-B27 is strongly associated with seronegative spondyloarthropathies including ankylosing spondylitis and reactive arthritis. Although of unknown aetiology, one hypothesis suggests that a cytotoxic T cell (CTL) response against a self-antigen at sites of inflammation, such as entheses or joints may be involved. The chondrocyte is one of the major specialized cell types found both in articular cartilage and cartilaginous entheses and therefore is a possible source of such an antigen. CTL recognition of these cells is a potential mechanism for inflammation and cartilage damage, both through direct lysis of chondrocytes and the secretion of pro-inflammatory cytokines such as tumour necrosis factor and interferon-gamma (IFN-gamma). We test the feasibility of this hypothesis by examining the ability of chondrocytes to present antigen to CTL in vitro. Chondrocytes isolated from the ribcages of mice did not constitutively express detectable levels of MHC class I by fluorescence-activated cell sorting analysis. In addition, they were resistant to lysis by alloreactive and influenza A virus nucleoprotein (NP)-specific CTL. However, treatment of chondrocytes with IFN-gamma up-regulated MHC class I expression and rendered the cells susceptible to lysis by CTL. Similarly, IFN-gamma-treated chondrocytes infected with influenza A virus were recognized by NP-specific CTL, though with variable efficiency. Thus, we suggest that under certain circumstances CTL-mediated lysis of chondrocytes is potentially a potent mechanism for cartilage damage in vivo, but that low levels of MHC class I on healthy chondrocytes protects from immune recognition in health.


Investigation of the Molecular Details of the Interactions of Selenoglycosides and Human Galectin-3.
Human galectin-3 (hGal-3) is involved in a variety of biological processes and is implicated in wide range of diseases. As a result, targeting hGal-3 for clinical applications has become an intense area of research. As a step towards the development of novel hGal-3 inhibitors, we describe a study of the binding of two Se-containing hGal-3 inhibitors, specifically that of di(β-D-galactopyranosyl)selenide (SeDG), in which two galactose rings are linked by one Se atom and a di(β-D-galactopyranosyl)diselenide (DSeDG) analogue with a diseleno bond between the two sugar units. The binding affinities of these derivatives to hGal-3 were determined by 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy titrations in solution, indicating a slight decrease in the strength of interaction for SeDG compared to thiodigalactoside (TDG), a well-known inhibitor of hGal-3, while DSeDG displayed a much weaker interaction strength. NMR and FA measurements showed that both seleno derivatives bind to the canonical S face site of hGal-3 and stack against the conserved W181 residue also confirmed by X-ray crystallography, revealing canonical properties of the interaction. The interaction with DSeDG revealed two distinct binding modes in the crystal structure which are in fast exchange on the NMR time scale in solution, explaining a weaker interaction with hGal-3 than SeDG. Using molecular dynamics simulations, we have found that energetic contributions to the binding enthalpies mainly differ in the electrostatic interactions and in polar solvation terms and are responsible for weaker binding of DSeDG compared to SeDG. Selenium-containing carbohydrate inhibitors of hGal-3 showing canonical binding modes offer the potential of becoming novel hydrolytically stable scaffolds for a new class of hGal-3 inhibitors.


B-cell-activating factor in rituximab-treated patients with anti-MAG polyneuropathy.
Antimyelin-associated glycoprotein (MAG) polyneuropathy is a slowly progressive distal form of mixed motor-sensory polyneuropathy that is scarcely responsive to conventional immunosuppressive therapy. Rituximab, a B-cell depleting antibody, is a promising therapeutic choice for anti-MAG polyneuropathy, and the evaluation of factors, such as B-cell-activating factor (BAFF), that control B-cell homeostasis is important to understand how this drug works. Using an ELISA method, the authors measured serum BAFF concentrations in 23 patients with anti-MAG polyneuropathy, before and after rituximab therapy, in 20 neurological controls and in 14 healthy subjects. The patients were followed up over a mean period of 38±12 months and categorised as responders/non-responders, and, between the responders, as relapsing/non-relapsing. Pretherapy serum BAFF concentrations in non-responders were higher than in responders (cut-off 1665 pg/ml; sensitivity 71.4%; specificity 93.7%; likelihood ratio 11.4), with the highest post-therapy increases in responders. In the responders who relapsed, relapses occurred when serum BAFF concentrations returned to baseline values, 1-2 years after blood B-cell reappearance. Before and during therapy, measurements of serum BAFF in rituximab-treated patients with anti-MAG polyneuropathy may help predict the response to the therapy. The findings in this study also provide information about rituximab-induced modifications on B-cell homeostatic regulation.


Multi-Hollow Surface Dielectric Barrier Discharge for Bacterial Biofilm Decontamination.
The plasma-activated gas is capable of decontaminating surfaces of different materials in remote distances. The effect of plasma-activated water vapor on Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli biofilm contamination was investigated on the polypropylene nonwoven textile surface. The robust and technically simple multi-hollow surface dielectric barrier discharge was used as a low-temperature atmospheric plasma source to activate the water-based medium. The germicidal efficiency of short and long-time exposure to plasma-activated water vapor was evaluated by standard microbiological cultivation and fluorescence analysis using a fluorescence multiwell plate reader. The test was repeated in different distances of the contaminated polypropylene nonwoven sample from the surface of the plasma source. The detection of reactive species in plasma-activated gas flow and condensed activated vapor, and thermal and electrical properties of the used plasma source, were measured. The bacterial biofilm decontamination efficiency increased with the exposure time and the plasma source power input. The log reduction of viable biofilm units decreased with the increasing distance from the dielectric surface.


HIV-related politics in long-term perspective.
Some long-term, large-scale socio-economic changes may affect the politics of HIV and other emerging viruses such as hepatitis C. It is useful to ask why the potential peace dividend of the early 1990s failed to provide adequate resources for HIV-related social and medical service delivery in developed or developing nations. This failure can be understood by looking at long-term global economic trends and the pressures they put on governments and corporations. They have produced a period in which fundamental issues of political and economic structure are at stake and, often, the response is a divide-and-rule politics to promote stability. National politics differ in terms of the extent to which such a 'politics of scapegoating' is institutionalized and in terms of which groups are scapegoated. Groups such as drug injectors, gay and bisexual men and sex traders are particularly likely to be targeted both by the scapegoaters and by HIV. Given this framework, how should public health professionals and activists engaged in HIV-related issues respond? Under what circumstances should we orient efforts upwards towards corporate, political or bureaucratic leaders? Under what circumstances, and how, should we orient towards popular forces? Relatedly, we need to consider an issue we often ignore: What do we have to offer potential allies? That is, in terms of their goals, philosophies and needs, why should they ally with us?


Experimental infection of murine and human macrophages with Cystoisospora belli.
Extraintestinal cystoisosporosis by Cystoisospora belli has already been reported in HIV/AIDS patients, generally involving preferential invasion of mesenteric and trachaeobronchial lymph nodes, liver and spleen by unizoic cysts of this parasite, which may infect macrophages. To test this hypothesis, murine and human macrophages were exposed to sporozoites of C. belli and cultures were observed daily after contact with these cells. The parasites penetrated and multiplied by endodyogeny in both cell types and inserted themselves inside perinuclear vacuoles. After 48 h, extracellular parasites were removed from macrophage cultures and incubated in Monkey Kidney Rhesus cells (MK2) where there was intense multiplication. This is the first report of infection of macrophages by this parasite, which supports the hypothesis that these could act as C. belli host cells in extraintestinal sites.


[Hypothyroid goiter with tracheal compression in a child in Cote d'Ivoire].
The purpose of this report is to describe a case involving a primary form of hypothyroid goiter with tracheal compression discovered late in a four-year-old child. Slowing of height and weight gain and mental retardation was irreversible. The child was treated using L-thyroxin. Systematic screening for hypothyroidism during the neonatal period is recommended in developing countries.


Mechanical ventilation: let us minimize sleep disturbances.
This review provides a background in mechanical ventilation and sleep. Sleep pattern in mechanically ventilated patients differs largely from physiological sleep. The ventilatory mode and the ventilatory settings could have an influence on the sleep quality and quantity. Pressure support ventilation can increase the sleep fragmentation and decrease the sleep quantity, due to central apneas when compared with assist control ventilation. An excessive level of ventilatory assistance during sleep promotes central apneas and ineffective efforts. These two respiratory events can trigger arousals and awakenings, thus altering the sleep quality and quantity in mechanically ventilated patients. Ventilatory settings adjusted according to the patient's effort during pressure support allow reducing the number of ineffective efforts and improve sleep quality when compared with a clinical adjustment. A physiological approach to set the ventilator and the ventilatory mode may improve sleep quality and quantity. Minimizing the sleep alterations in mechanically ventilated patients could be obtained by setting the ventilator in such a way to avoid hyperventilation during the sleep stage. The impact of sleep derangements in patient outcomes is, however, unknown.


[Congenital heart diseases in women].
Are there gender differences in prevalence, surgical results and long-term survival of patients with congenital heart disease? Available literature data allow us to state what follows. At birth there is a mild but significant prevalence of congenital heart disease in females. The most severe congenital heart diseases are less frequent in girls, but when they are present in females, they are linked to a higher surgical mortality rate, due perhaps to lower weight at birth and to the prevalence of extracardiac malformations and/or of associated genetic syndromes. On the other hand, in adults, surgery for congenital heart disease is at higher risk in males, and so the long-term survival rate is higher in females. Particular psychological attitudes, a higher incidence of pulmonary hypertension, as well as specific problems linked to the reproductive function characterize congenital heart disease in adult women. The knowledge and analysis of these data are essential for a correct management of congenital heart disease in neonates, children and adults.


MicroRNAs in ankylosing spondylitis: Function, potential and challenges.
Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA, are considered the essential connection between a disorder's onset and the environment, on a permissive genetic background. Among autoimmune and inflammatory-mediated disorders, Ankylosing Spondylitis (AS), a chronic arthritis of the spine, is a very good example for the weight of epigenetics' contribution. MicroRNAs (miRNAs) are single-stranded nucleotides which regulate gene expression and are involved in pathological and physiological processes. In this manuscript we provide a clarification on the role of microRNAs in AS, with a focus on the mechanisms of pathogenesis. In specific, we have examined the contribution of miRNAs in the processes of inflammation, new bone formation and T-cell function, and the pathways (i.e. Wnt, BMP, TGFβ signalling etc.) they regulate. The utility of miRNAs in better understanding AS pathogenesis is undisputed and their utility as therapeutic opportunity is strongly increasing.


Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome.
CD40L and B lymphocyte-activating factor (BAFF), members of the TNF superfamily, play critical roles in B cell survival and activation, and in the regulation of humoral immunity. We previously reported that the adaptor molecule Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival. Here we demonstrated that mice deficient in Act1 developed systemic autoimmune disease with histological and serological features of human Sjögren's syndrome (SS), in association with systemic lupus erythematosus-like nephritis. Analyses of Act1(-/-)CD40(-/-) and Act1(-/-)BAFF(-/-) double-deficient mice revealed that Act1 regulates different stages of the disease development through its impact on both CD40- and BAFF-mediated pathways. We found that Act1 modulates the survival of autoreactive B cells mainly through its negative regulatory role in BAFF-mediated cell survival, while the effect of Act1 on autoantibody production is likely through modulation of CD40-mediated T cell-dependent antibody response. The impact of Act1 on both BAFF and CD40 pathways establishes Act1-deficient mice as a unique model to study distinct steps of autoimmunity and regulation of self tolerance.


[Psychophysiologic characteristics of the individual psychotropic activity of benzodiazepine derivatives under experimental conditions].
In 156 experiments performed on 41 cats with adequate experimental models of pseudoneurotic conditions, states of anxiety due to an electrostimulation of the hypothalamus through implanted electrodes and an emotional stress due to a conflict situation the authors compared the individual traits of the psychotropic activity of lorazepam, diazepam, chlordiazepoxide, oxazepam, nirazepam. These experiments permitted to display significant differences of psychophysiological structures in the tranquilizing effect of 5 benzodiazepine derivatives.


Surgical advances in treating otitis media.
Surgical methods of treating otitis media and its sequelae are discussed, according to the classification of otitis media presented in an earlier report. Surgical management of otitis media with effusion and recurrent purulent otitis media includes myringotomy and use of ventilation tubes. Occasionally, otitis media with effusion will lead to structural and other pathologic changes in the middle ear, and conservative treatments such as use of medication or tubes will not suffice. Indications and methods for exploratory tympanotomy and reconstruction of the middle ear are discussed. In such instances, tympanoplasty can be used to the patient's benefit. Chronic otitis media with mastoiditis, defined by the presence of intractable pathologic tissue, generally requires surgical correction. Classic methods include simple mastoidectomy, modified radical (Bondy) mastoidectomy, and radical mastoidectomy. Current classifications of procedures would also include closed-cavity tympanomastoidectomy, open-cavity tympanomastoidectomy, and intact-bridge tympanomastoidectomy (a combined approach). The diagnostic and surgical approach to silent or subclinical otitis media is discussed. Diagnosis and treatment of sequelae of otitis media, including sequelae in the middle ear and, less commonly, in the inner ear, are discussed.


Localization of the death effector domain of Fas-associated death domain protein into the membrane of Escherichia coli induces reactive oxygen species-involved cell death.
The death effector domain (DED) of the mammalian apoptosis mediator, Fas-associated death domain protein (FADD), induces Escherichia coli cell death under aerobic culture conditions, yet the mechanisms by which FADD-DED induces cell death are not fully understood. Oxidative stress has been implicated as one of the mechanisms. Using a proteomic approach and validation by coexpression analysis, we illustrate that overexpression of FADD-DED in E. coli invokes protein expression changes that facilitate conversion of pro-oxidant NADH into antioxidant NADPH. Typically, isocitrate dehydrogenase, phosphoenolpyruvate carboxykinase, and pyruvate kinase are downregulated and malate dehydrogenase is upregulated. We reasoned that such a change in E. coli cells is an active response to reduce the size of the NADH pool, thereby decreasing the level of ROS generation. From the coexpression studies, we observed that DNA binding protein Hns, which induces growth arrest when overexpressed heterologously, alleviated the cell killing effect of FADD-DED. FADD-DED was expressed as a noncovalently linked multimeric protein in the membrane of E. coli. Exogenous treatment of E. coli cells with FADD-DED in the presence of a membrane component induced cell death, which was accompanied by a shift of the redox balance and a decrease in the cellular ATP level. Cell death was blocked by prior expression of thioredoxin. Localization of FADD-DED to the membrane may shift the cells into a state that stimulates and fuels ROS generation. The cell death mechanism mediated by ROS may mimic antibiotic-mediated bacterial cell death or Bax-mediated apoptosis in mammalian cells. Our results provide a common mechanistic feature of ROS-involved cell death throughout prokaryotes and eukaryotes.


Noise-induced hearing loss still a problem in shipbuilders: a cross-sectional study in goa, India.
Workplace safety regulations seek to mitigate noise-induced hearing loss (NIHL), conventionally associated with the shipbuilding industry. Despite this, are workers still predisposed to NIHL? To study the prevalence of NIHL among noise-exposed subjects in the shipbuilding industry in Goa and to compare it with that among the non-exposed population working in the same industry in relation to certain relevant factors. This is a cross-sectional study in the shipbuilding industry, Goa This study examined 552 workers: 276 shipbuilders and 276 office staff, of similar age, duration of employment and socio-economic status working at a shipbuilding enterprise. An interviewer-administered questionnaire was followed by audiometry. Values were presented as percentages, Mean (SD) and odds ratio (OR) and its 95% confidence interval (CI) (Woolfe's method). Fisher's exact test and binary logistic regression were used. P value of < 0.05 was taken as significant. SPSS version 16 was used. NIHL was found in 17 (6%) shipbuilders, while no office staff was detected to have this condition (OR = 37.29, 95% CI 22.42-62.18). The shipbuilders with NIHL were 52.5 years of age and had been employed for 30.4 years, on an average. None of the 17 cases of NIHL were found to be using earplugs consistently; 11 reported using them "sometimes" and six "never" used them. NIHL continues to affect shipbuilders, owing their non-compliance to workplace regulation. Health education is the need of the hour.


Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition.
Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases axonal mitochondrial transport. HDAC6 inhibition increases acetylated Miro1 in axons, and acetyl-mimetic Miro1 K105Q prevents CSPG-dependent decreases in mitochondrial transport and axon growth. MAG- and CSPG-dependent deacetylation of Miro1 requires RhoA/ROCK activation and downstream intracellular Ca2+ increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca2+ These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport.


A prospective study of XRCC1 haplotypes and their interaction with plasma carotenoids on breast cancer risk.
The XRCC1 protein is involved in the base excision repair pathway through interactions with other proteins. Polymorphisms in the XRCC1 gene may lead to variation in repair proficiency and confer inherited predisposition to cancer. We prospectively assessed the associations between polymorphisms and haplotypes in XRCC1 and breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n = 1004; controls, n = 1385). We further investigated gene-environment interactions between the XRCC1 variations and plasma carotenoids on breast cancer risk. We genotyped four haplotype-tagging single nucleotide polymorphisms (Arg(194)Trp, C26602T, Arg(399)Gln, and Gln(632)Gln) in the XRCC1 gene. Five common haplotypes accounted for 99% of the chromosomes in the present study population of mostly Caucasian women. We observed a marginally significant reduction in the risk of breast cancer among (194)Trp carriers. As compared with no-carriers, women with at least one (194)Trp allele had a multivariate odds ratio of 0.79 (95% of the confidence interval, 0.60-1.04). The inferred haplotype harboring the (194)Trp allele was more common in controls than in cases (6.6 versus 5.3%, P = 0.07). We observed that the Arg(194)Trp modified the inverse associations of plasma alpha-carotene level (P, ordinal test for interaction = 0.02) and plasma beta-carotene level (P, ordinal test for interaction = 0.003) with breast cancer risk. No suggestion of an interaction was observed between the Arg(194)Trp and cigarette smoking. Our results suggest an inverse association between XRCC1 (194)Trp allele and breast cancer risk. The findings of the effect modification of the Arg(194)Trp on the relations of plasma alpha- and beta-carotene levels with breast cancer risk suggest a potential protective effect of carotenoids in breast carcinogenesis by preventing oxidative DNA damage.


Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders.
KIT is a member of the tyrosine kinase family of growth factor receptors which is expressed on a variety of haematopoietic cells including mast cells. Stem cell factor (SCF)-dependent activation of KIT is critical for mast cell homeostasis and function. However, when KIT is inappropriately activated, accumulation of mast cells in tissues results in mastocytosis. Such dysregulated KIT activation is a manifestation of specific activating point mutations within KIT, with the human D816V mutation considered as a hallmark of human systemic mastocytosis. A number of other activating mutations in KIT have recently been identified and these mutations may also contribute to aberrant mast cell growth. In addition to its role in mast cell growth, differentiation and survival, localized concentration gradients of SCF may control the targeting of mast cells to specific tissues and, once resident within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders.


[Organ shortage in transplant centers--approaches to a solution from the economic viewpoint].
In the article the regulations of the German transplantation law, which came into force on 1 December 1997, are considered from an economic perspective. First, the essential regulations of the law are described and then analyzed with respect to economic aspects. The law regulates in particular the administration of the demand surplus for organs. This could be reduced by rationing the demand or by increasing the supply. Apart from the medical features economic attributes such as cost effectiveness are also applicable as criteria for rationing. In addition, the method of the quality-adjusted life-years (QALYs) is introduced and described on the basis of the results of a study about costs and benefits of liver transplantation. To increase the organ supply the authorities in Germany have so far established information campaigns and made appeals to the public. In contrast, an organ donation club the allocation of donors is made considering if and when the recipient declared his readiness to organ donation. In this way the willingness to donate his own organs could be sanctioned positively and an additional incentive for supply could be set.


Half-sandwich ruthenium(ii) complexes with tethered arene-phosphinite ligands: synthesis, structure and application in catalytic cross dehydrogenative coupling reactions of silanes and alcohols.
The preparation of the tethered arene-ruthenium(ii) complexes [RuCl2{η6:κ1(P)-C6H5(CH2)nOPR2}] (R = Ph, n = 1 (9a), 2 (9b), 3 (9c); R = iPr, n = 1 (10a), 2 (10b), 3 (10c)) from the corresponding phosphinite ligands R2PO(CH2)nPh (R = Ph, n = 1 (1a), 2 (1b), 3 (1c); R = iPr, n = 1 (2a), 2 (2b), 3 (2c)) is presented. Thus, in a first step, the treatment at room temperature of tetrahydrofuran solutions of dimers [{RuCl(μ-Cl)(η6-arene)}2] (arene = p-cymene (3), benzene (4)) with 1-2a-c led to the clean formation of the corresponding mononuclear derivatives [RuCl2(η6-p-cymene){R2PO(CH2)nPh}] (5-6a-c) and [RuCl2(η6-benzene){R2PO(CH2)nPh}] (7-8a-c), which were isolated in 66-99% yield. The subsequent heating of 1,2-dichloroethane solutions of these compounds at 120 °C allowed the exchange of the coordinated arene. The substitution process proceeded faster with the benzene derivatives 7-8a-c, from which complexes 9-10a-c were generated in 61-82% yield after 0.5-10 h of heating. The molecular structures of [RuCl2(η6-p-cymene){iPr2PO(CH2)3Ph}] (6c) and [RuCl2{η6:κ1(P)-C6H5(CH2)nOPiPr2}] (n = 1 (10a), 2 (10b), 3 (10c)) were unequivocally confirmed by X-ray diffraction methods. In addition, complexes [RuCl2{η6:κ1(P)-C6H5(CH2)nOPR2}] (9-10a-c) proved to be active catalysts for the dehydrogenative coupling of hydrosilanes and alcohols under mild conditions (r.t.). The best results were obtained with [RuCl2{η6:κ1(P)-C6H5(CH2)3OPiPr2}] (10c), which reached TOF and TON values up to 117 600 h-1 and 57 000, respectively.


Estimation of a non-parametric variable importance measure of a continuous exposure.
We define a new measure of variable importance of an exposure on a continuous outcome, accounting for potential confounders. The exposure features a reference level x(0) with positive mass and a continuum of other levels. For the purpose of estimating it, we fully develop the semi-parametric estimation methodology called targeted minimum loss estimation methodology (TMLE) [23, 22]. We cover the whole spectrum of its theoretical study (convergence of the iterative procedure which is at the core of the TMLE methodology; consistency and asymptotic normality of the estimator), practical implementation, simulation study and application to a genomic example that originally motivated this article. In the latter, the exposure X and response Y are, respectively, the DNA copy number and expression level of a given gene in a cancer cell. Here, the reference level is x(0) = 2, that is the expected DNA copy number in a normal cell. The confounder is a measure of the methylation of the gene. The fact that there is no clear biological indication that X and Y can be interpreted as an exposure and a response, respectively, is not problematic.


The burden of childhood influenza in a tertiary paediatric setting.
Influenza is usually considered a mild winter-time illness but can be associated with a range of serious complications. We undertook a retrospective medical record review to study the impact of admissions of children with laboratory-confirmed influenza to The Children's Hospital at Westmead, Sydney, during 2007. One hundred and twenty-two children were identified, representing 530 hospital admission days. There was no clearly documented evidence of influenza vaccination for any patient eligible for vaccination. Fever (97.5%) and cough (69.7%) were the most frequent manifestations. Admissions occurred almost entirely between June and September with a peak in July (n=61, 50%). Two-thirds of the children were aged less than 2 years (median 1.5 years). Most (61.5%) had an underlying chronic medical disorder. Lumbar puncture was performed in 28 (23%) children, mostly infants aged less than 3 months (n=18). Antibiotics were commonly prescribed (67.2%), but use of available influenza-specific antiviral agents was uncommon (13.1%). The nosocomial infection rate was 9.8% and the clinical staff vaccination rate was low (less than 30%). Pneumonia was the most common complication (12.3%). No influenza-related deaths occurred. Influenza in young children poses a significant burden to health care services, tertiary admissions representing the tip-of-the-iceberg. Vaccination rates are inappropriately low in both eligible patients and hospital clinical staff. Early 'point of care' testing, use of influenza-specific antiviral agents, and extension of current vaccination schedules to include all children aged six to 23 months could considerably reduce over-investigation, unnecessary use of antibiotics and the health care impact of influenza.


Knowledge based cluster ensemble for cancer discovery from biomolecular data.
The adoption of microarray techniques in biological and medical research provides a new way for cancer diagnosis and treatment. In order to perform successful diagnosis and treatment of cancer, discovering and classifying cancer types correctly is essential. Class discovery is one of the most important tasks in cancer classification using biomolecular data. Most of the existing works adopt single clustering algorithms to perform class discovery from biomolecular data. However, single clustering algorithms have limitations, which include a lack of robustness, stability, and accuracy. In this paper, we propose a new cluster ensemble approach called knowledge based cluster ensemble (KCE) which incorporates the prior knowledge of the data sets into the cluster ensemble framework. Specifically, KCE represents the prior knowledge of a data set in the form of pairwise constraints. Then, the spectral clustering algorithm (SC) is adopted to generate a set of clustering solutions. Next, KCE transforms pairwise constraints into confidence factors for these clustering solutions. After that, a consensus matrix is constructed by considering all the clustering solutions and their corresponding confidence factors. The final clustering result is obtained by partitioning the consensus matrix. Comparison with single clustering algorithms and conventional cluster ensemble approaches, knowledge based cluster ensemble approaches are more robust, stable and accurate. The experiments on cancer data sets show that: 1) KCE works well on these data sets; 2) KCE not only outperforms most of the state-of-the-art single clustering algorithms, but also outperforms most of the state-of-the-art cluster ensemble approaches.


Mechanical atrial recovery after cardioversion in persistent atrial fibrillation evaluated by bidimensional speckle tracking echocardiography.
Atrial fibrillation induces reversible electrical and mechanical modifications (atrial remodeling). Atrial stunning is a mechanical dysfunction with preserved bioelectrical function, occurring after successful atrial fibrillation electrical cardioversion (ECV). Two-dimensional speckle tracking echocardiography is a new technology for evaluating atrial mechanical function. We assessed atrial mechanical function after ECV with serial two-dimensional speckle tracking echocardiography evaluations. The investigated outcome was left atrium mechanical recovery within 3 months. A total of 36 patients [mean age 73 (7.9) years, 23 males] with persistent atrial fibrillation underwent conventional transthoracic and transesophageal echocardiography before ECV. Positive global atrial strain (GSA+) was assessed at 3 h, 1, 2, 3, 4 weeks and 3 months after ECV. Mechanical recovery was defined as the achievement of a GSA+ value of 21%. Independent predictors of GSA+ immediately after ECV (basal GSA+) were E/e' ratio and left atrial appendage anterograde flow velocity. During the follow-up, 25% of patients suffered atrial fibrillation recurrence. In 12/36 patients (33%) left atrium mechanical recovery was detected (mechanical recovery group), while in 15/36 (42%) recovery did not occur (no atrial mechanical recovery group). At univariate analysis, the variables associated with recovery, were basal GSA+ (P = 0.015) and maximal velocity left atrial appendage (P = 0.022). Female sex (P = 0.038), N-terminal pro-B type natriuretic peptide (P = 0.013), E/e' (P = 0.042) and the indexed left atrium volume (P = 0.019) were associated with the lack of left atrium mechanical recovery. In almost half of the patients, the left atrium did not resume mechanical activity within the 3 months after ECV, despite sinus rhythm recovery. The left atrium of these patients was larger, stiffer and their E/E' was higher, suggesting a higher endocavitary pressure compared with mechanical recovery patients. These findings might suggest an increased thromboembolic risk.