Functional status and radiographic joint damage are associated with health economic outcomes in patients with rheumatoid arthritis.
This analysis examines the relationship between the functional and radiographic measures of disease activity and the employment status in patients with rheumatoid arthritis (RA). We also assessed the influence of improvement in physical function on employability, healthcare costs, and quality of life, utilizing data collected in the ATTRACT trial. During the ATTRACT trial, the Health Assessment Questionnaire (HAQ) disability index, radiographic damage measured by the van der Heijde modified Sharp (vdH-Sharp) score, employment status, healthcare resource utilization, and quality of life measured by Medical Outcomes Survey Short Form-36 were assessed at baseline and again periodically through Week 54. Clinically important improvement was defined as an improvement in the HAQ of > or = 0.25 from baseline to Week 54. There was a significant association at baseline between functional status and the percentages of patients employed. Increased radiographic joint damage was associated with lower full-time employment rate, with patients in the 2 highest quartiles (vdH-Sharp score > 51.5) of radiographic damage having lower rates of full-time employment than those with less damage. During the ATTRACT trial, patients who achieved a clinically important improvement in HAQ scores had a significant improvement in their employability (21% vs 3%; p < 0.001), in their time lost from work (7 vs 30 days; p = 0.012), in their total/direct medical costs (7093/6791 US dollars vs 11,712/10,039 US dollars; p < 0.001), and in their quality of life (p < 0.001) compared with those who did not demonstrate this improvement. Functional disability and radiographic joint damage are correlated with employment in patients with RA. Clinically important improvement in HAQ scores is associated with substantial health economic and quality of life benefits for patients with RA.


Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review.
Objective: To systematically assess benefits and harm of non-pharmacologic interventions for diabetic peripheral neuropathy (DPN) symptoms.Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from 1966 to May 24, 2016 for randomized controlled trials. Two reviewers evaluated studies for eligibility, serially abstracted data, evaluated risk of bias, and graded strength of evidence (SOE) for critical outcomes (pain and quality-of-life).Results: Twenty-three trials were included. For pain, alpha-lipoic acid was more effective than placebo (moderate SOE) and frequency-modulated electromagnetic stimulation was more effective than sham (low SOE) in the short-term but not the long-term. Electrical stimulation (including transcutaneous) was not effective for pain (low SOE). Spinal cord stimulation was more effective than usual care for pain (low SOE), but had serious complications, and studies had no sham arm. Evidence for cognitive behavioral therapy and acupuncture was insufficient; no exercise or physical therapy trials met inclusion criteria. No interventions reported sufficient evidence on quality-of-life. Most studies were short-term with unclear risk of bias.Conclusions: Alpha-lipoic acid and spinal cord stimulation were effective for pain; studies were short-term with quality deficits. Spinal cord stimulation had serious adverse events. Further research should address long-term outcomes and other non-pharmacologic treatments.


Epidemiology of echinococcosis in Kazakhstan: an update.
Kazakhstan is highly endemic for echinococcosis. Both Echinococcus granulosus and E. multilocularis are widely distributed in the country. Official records of human cystic echinococcosis over the past 5-10 years suggest a stable incidence of approximately 800-1000 cases per year, which is 5 cases per 100,000 per year. This followed a rapid increase in the incidence following the dissolution of the Soviet Union. Between 2007 and 2013, 5949 cases were reported in the national surveillance data. The prevalence in sheep, based on slaughterhouse studies, suggests that between 30 and 50% of sheep are infected with hydatid cysts, while cattle have a prevalence of approximately 7%. Rural dogs have a high prevalence of infection of between 5 and 10%, with shepherd dogs having prevalences of over 20%. G1 and G6/7 strains of E. granulosus have been isolated from dogs in Kazakhstan. Wolves are also infected, with one prevalence estimate of approximately 20%. The incidence of human alveolar echinococcosis is less clear, although estimates from Kazakhstani expatriates living in Germany and the hospital records of a single referral centre in Almaty suggest 34 or 130 cases per year (or an annual incidence of 0.20 or 0.76 cases per 100,000), respectively, could be occurring in Kazakhstan. Studies suggest that in some rural dog populations the prevalence may be about 5%. The parasite is widely distributed in foxes and small mammals through much of Kazakhstan.


Assessing validity and reliability of Dundee ready educational environment measure (DREEM) in Iran.
If an institute is looking for improvement of its learning environment, a reliable and valid assessment tool is needed for measurement of the educational environment .The Dundee Ready Educational Environment Measure (DREEM) has been used in various studies to evaluate the educational environment. However, psychometric evaluations of the instrument seem necessary, for all known versions of the instrument. The aim of this study was to investigate the reliability and validity of Persian version of the DREEM in the major clinical wards in teaching hospitals affiliated to Iran University of Medical Sciences. This descriptive - analytical study, involved medical students (clinical stagers and interns) in 4 major clinical wards. In this study, DREEM questionnaire was reviewed in content, face validity and construct validity through confirmatory factor analysis. The reliability was calculated according to test - retest and the internal consistency was measured using Cronbach's alpha coefficient. A total number of 267 questionnaires were completed by medical stagers (60%) and interns (40%) including 181 females and 82 males. The mean age of stagers and interns were 23.60 ± 1.27 and 25.45 ± 1.22 years, respectively. The total mean of the questionnaire was calculated as 96.15 (93.5375, 98.7547) out of 176, with 95% confidence interval. The face validity of the questionnaire was confirmed. The mean of content validity ratio (CVR) was calculated as 0.35, and 6 questions were omitted in this step. The content validity index (CVI) was 0.39. The reliability coefficient mean was 0.71. In confirmatory factor analysis five factors were confirmed that changed the orientation of some questions. The Cronbach's alpha coefficient of the whole questionnaire was obtained as 0.914. The modified and validates DREEM questionnaire in Persian language with 44 items and appropriate psychometric attributes is capable of being used in assessment of clinical education environments in Iran.


Involvement of nuclear factor-kappaB in the inhibition of interleukin-12 production from mouse macrophages by baicalein, a flavonoid in Scutellaria baicalensis.
Pharmacological inhibition of interleukin-12 (IL-12) production may be a therapeutic strategy for preventing development and progression of disease in experimental models of autoimmunity. In this study we investigated the effects of baicalein, a flavonoid present in the root of Scutellaria baicalensis, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). Baicalein potently inhibited the LPS-induced IL-12 production from both primary macrophages and RAW264.7 monocytic cell-line in a dose-dependent manner (the IC50 values were 43.7 and 17.4 microM, respectively). The effect of baicalein on IL-12 gene promoter activation was analyzed by transfecting RAW264.7 cells with IL-12 gene promoter/luciferase constructs. The repressive effect mapped to a region in the IL-12 gene promoter containing a binding site for NF-kappaB. Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the NF-kappaB site, which significantly decreased upon addition of baicalein, indicating that baicalein inhibited IL-12 production in LPS-activated macrophages via inhibition of NF-kappaB binding activity.


An initial overestimation of sensorineural hearing loss in NICU infants after failure on neonatal hearing screening.
Infants admitted to neonatal intensive care units have a higher incidence of significant congenital hearing loss. We classified audiologic diagnoses and follow-up in infants who had been admitted to our neonatal intensive care unit. We included all infants admitted to the neonatal intensive care unit at Sophia Children's Hospital between 2004 and 2009 who had been referred for auditory brainstem response measurement after failing neonatal hearing screening with automated auditory brainstem response. We retrospectively analyzed the results of auditory brainstem response measurement. Between 2004 and 2009 3316 infants admitted to our neonatal intensive care unit had neonatal hearing screening. 103 infants failed neonatal hearing screening: 46 girls and 57 boys. After first auditory brainstem response measurement we found 18% had normal hearing or a minimal hearing loss. The remainder had a type of hearing loss, distributed as follows: 15% conductive, 32% symmetric sensorineural, 14% asymmetric sensorineural, and 21% absent auditory brainstem responses. Repeated auditory brainstem response measurement showed a shift in hearing outcome. The main difference was an improvement from symmetric sensorineural hearing loss to normal hearing. However, in a small percentage of children, the hearing deteriorated. As many as 58% of infants in this high-risk population who failed the neonatal hearing screening were diagnosed with sensorineural hearing loss or absent auditory brainstem responses. An initial overestimation of sensorineural hearing loss of about 10% was seen at first auditory brainstem response measurement. This may be partially explained by a conductive component that has resolved. Finally, in a small percentage of children the hearing deteriorated.


The protective effects of exercise and phosphoinositide 3-kinase (p110alpha) in the failing heart.
Despite the development of a wide range of therapies, heart failure remains a leading cause of death in Western society. New therapies are needed to help combat this debilitating condition. Exercise is becoming an increasingly important feature of rehabilitation programmes for patients with heart failure. Before the 1980s, patients with heart failure were advised not to exercise as it was thought that exercise would increase the risk of a cardiac event (such as myocardial infarction). However, in recent years both aerobic and resistance training have been shown to be safe and beneficial for patients with heart failure, improving exercise tolerance and quality of life, and preventing muscular deconditioning. The molecular mechanisms responsible for exercise-induced cardioprotection are yet to be elucidated, however studies in transgenic mice have identified PI3K(p110alpha) (phosphoinositide 3-kinase p110alpha) as a likely mediator. PI3K(p110alpha) is a lipid kinase which is activated in the heart during chronic exercise training, and is important for maintaining heart structure and function in various pathological settings. In the present review the protective effects of PI3K(p110alpha) in the failing heart and its potential as a therapeutic strategy for the treatment of heart failure is discussed.


Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood.
microRNA (miRNA) are small non-coding RNA species that are transcriptionally processed in the host cell and released extracellularly into the bloodstream. Normally involved in post-transcriptional gene silencing, the deregulation of miRNA has been shown to influence pathogenesis of a number of diseases. Next-generation deep sequencing (NGS) has provided the ability to profile miRNA in biological fluids making this approach a viable screening tool to detect miRNA biomarkers. However, collection and handling procedures of blood needs to be greatly improved for miRNA analysis in order to reliably detect differences between healthy and disease patients. Furthermore, ribonucleases present in blood can degrade RNA upon collection rendering extracellular miRNA at risk of degradation. These factors have consequently decreased sensitivity and specificity of miRNA biomarker assays. Here, we use NGS to profile miRNA in various blood components and identify differences in profiles within peripheral blood compared to cell-free plasma or serum and extracellular vesicles known as exosomes. We also analyse and compare the miRNA content in exosomes prepared by ultracentrifugation methods and commercial exosome isolation kits including treating samples with RNaseA. This study demonstrates that exosomal RNA is protected by RNaseA treatment and that exosomes provide a consistent source of miRNA for disease biomarker detection.


Random lasing from granular surface of waveguide with blends of PS and PMMA.
Lasing from a planar waveguide with the blend of Polystyrene(PS): Poly-methylmethacrylate(PMMA) doped with tris(8-hydroxyquinolinato)aluminum(Alq(3)) and 4-(dicyanomethylene)-2-tert-butyl-6(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran(DCJTB) was investigated. Due to phase separation of the blend of PS:PMMA during the solvent evaporation process, a waveguide with granular surface was obtained, which has 2D island-like nanostructures with diameters ranging between 200 and 400 nm and heights at about 25 nm. Pumped by a YAG laser with wavelength of 355 nm, a significant random lasing was observed. Compared to the amplified spontaneous radiation (ASE) of planar waveguides with only PMMA or PS doped with Alq3:DCJTB prepared under the same conditions, the lasing threshold of the former is decreased by about 5 times, and the full width at half maximum (FWHM) is reduced to 1.7 nm from 12~15 nm. Our experiments show a promising method to achieve lower threshold for organic lasers.


Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.
The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.


Analytical modeling of the gas-filling dynamics in photonic crystal fibers.
We present useful expressions predicting the filling time of gaseous species inside photonic crystal fibers. Based on the theory of diffusion, this gas-filling model can be applied to any given fiber geometry or length by calculating diffusion coefficients. This was experimentally validated by monitoring the filling process of acetylene gas in several fiber samples of various geometries and lengths. The measured filling times agree well, within +/-15%, with the predicted values for all fiber samples. In addition, the pressure dependence of the diffusion coefficient was experimentally verified by filling a given fiber sample with acetylene gas at various pressures. Finally, optimized conditions for gas-light interaction are determined by considering the gas flow dynamics in the design of microstructured fibers for gas detection and all-fiber gas cell applications.


Resistance training predicts 6-yr body composition change in postmenopausal women.
The aim of this study was to examine the association of exercise frequency (ExFreq) and volume (total weight lifted by military press and squats (SQ)) with change in body composition among postmenopausal women participating in a progressive resistance training study. Previously, sedentary women (n = 122, age = 56.3 +/- 4.3 yr) were followed for 6 yr. At 6 yr, there were women who had been randomly assigned to resistance training at baseline (n = 65) controls that were permitted to cross over to the exercise program at 1 yr (n = 32) and 25 true controls. Exercisers and crossovers directed to perform eight core exercises for two sets of eight repetitions at 70%-80% of one-repetition maximum, three times weekly, plus progressive weight bearing, stretching, and balance. Body weight and fat were measured at baseline and annually using anthropometry and dual-energy x-ray absorptiometry. Average change in body weight and total body fat were 0.83 +/- 5.39 and 0.64 +/- 4.95 kg at 6 yr, respectively. In multiple linear regression, ExFreq, military press, and SQ were significantly inversely associated with change in body weight (standardized beta coefficient (SBC) = -0.22 to -0.28, P < 0.01), fat (SBC = -0.25 to -0.33, P < 0.01), and trunk fat (SBC = -0.20 to -0.31, P < 0.03) after adjusting for age, years on hormone therapy, change in lean soft tissue, baseline body composition, and baseline habitual exercise. The lowest tertile of SQ (equivalent to 2.5% attendance) demonstrated significant gain in weight, fat, and trunk fat over 6 yr (P < 0.004), whereas the highest tertile SQ (equivalent to 64% attendance) was able to maintain their weight, total, and regional fat. We conclude that resistance training is a viable long-term method to prevent weight gain and deleterious changes in body composition in postmenopausal women.


A multimedia intervention to support family caregivers.
The lack of choice and predominance of crisis-oriented care in relation to respite and long-term care for family carers and frail older people provided the authors with the rationale for the development, within the European-funded Assisting Carers using Telematic Interventions to meet Older person's Needs (ACTION) project, of two innovative multimedia programs. The key aim of the programs is to provide education, information, and support about respite care and planning for the future for family carers and frail older people in their homes. In this way, it is intended that family carers and frail older people will be able to make informed choices concerning their health and social care needs. The authors describe the conceptual basis of the multimedia programs, the research and development process, the content of the multimedia programs, and the evaluation of the developed product.


Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.


The history of the formation of the Pan African paediatric surgical Association (PAPSA).
Political change in the 1990s in Southern Africa influenced the long awaited formation of a children's surgical association in Africa. Here, within is the historical account of the formation of the Pan African Association of Paediatric Surgeons (PAPSA). The basis of the argument for the formation of PAPSA was that paediatric surgeons from Africa have a wealth of experience and special knowledge of diseases affecting children in the African continent which differ substantially from those encountered in other regions of the world. This historical account is mainly from documentation by 2 of the organisations founding members.


RADAR: a web server for RNA data analysis and research.
RADAR is a web server that provides a multitude of functionality for RNA data analysis and research. It can align structure-annotated RNA sequences so that both sequence and structure information are taken into consideration during the alignment process. This server is capable of performing pairwise structure alignment, multiple structure alignment, database search and clustering. In addition, RADAR provides two salient features: (i) constrained alignment of RNA secondary structures, and (ii) prediction of the consensus structure for a set of RNA sequences. RADAR will be able to assist scientists in performing many important RNA mining operations, including the understanding of the functionality of RNA sequences, the detection of RNA structural motifs and the clustering of RNA molecules, among others. The web server together with a software package for download is freely accessible at http://datalab.njit.edu/biodata/rna/RSmatch/server.htm and http://www.ccrnp.ncifcrf.gov/~bshapiro/


Helping Smokers Quit: New Partners and New Strategies from the University of California, San Francisco Smoking Cessation Leadership Center.
The Smoking Cessation Leadership Center (SCLC) was established in 2003 to increase the rate of smoking cessation attempts and the likelihood those efforts would succeed. Although smoking remains the number one cause of preventable death and disability, clinicians underperform in smoking cessation. Furthermore, many clinical organizations, governmental agencies, and advocacy groups put little effort into smoking cessation. Initially targeted at increasing the efforts of primary care physicians, SCLC efforts expanded to include many other medical and non-physician disciplines, ultimately engaging 21 separate specialties. Most clinicians and their organizations are daunted by efforts required to become cessation experts. A compromise solution, Ask, Advise, Refer (to telephone quitlines), was crafted. SCLC also stimulated smoking cessation projects in governmental, not-for-profit, and industry groups, including the Veterans Administration, the Health Resources Services Administration, Los Angeles County, and the Joint Commission. SCLC helped CVS pharmacies to stop selling tobacco products and other pharmacies to increase smoking cessation efforts, provided multiple educational offerings, and distributed $6.4 million in industry-supported smoking cessation grants to 55 organizations plus $4 million in direct SCLC grants. Nevertheless, smoking still causes 540,000 annual deaths in the US. SCLC's work in the field of behavioral health is described in a companion article.


Factors influencing the severity of menopause symptoms in Korean post-menopausal women.
We have relatively limited knowledge of symptomatic aspects of the postmenopause, rather than perimenopause. We tried to determine the factors associated with experiencing menopausal symptoms by Korean postmenopausal women. A total of 657 Korean women who underwent a natural menopause completed multiple questionnaires, which included questions regarding their attitudes to menopause, depressive symptoms, state anxiety, self-esteem, dyadic relationships, sociodemographic variables, and 11-item Menopause Rating Scale (MRS). Multiple regression analyses were performed to collectively examine the relative impact of each independent variable on the quality of life, as determined by the MRS. Decreased severity of menopausal symptoms was associated with more time spent in education, an employed status, a history of pregnancy, longer postmenopausal duration, positive attitudes to menopause, higher state anxiety, heightened self-esteem, and higher dyadic consensus. Increased severity of menopausal symptoms was also associated with absence of a partner, alcohol consumption, a history of hormone replacement therapy, a history of probable premenstrual dysphoric disorder, and increased severity of depressive symptoms. Sociodemographic characteristics, lifestyle factors, premenstrual dysphoric disorder, attitudes to menopause, a dyadic relationship with a partner, and the inner psychological status can be associated with the severity of menopause symptoms specifically in Korean postmenopausal women.


Stenting of symptomatic intracranial stenosis using balloon mounted coronary stents: a single center experience.
Intracranial atherosclerotic disease is the cause of up to 10% of ischemic strokes and transient ischemic attacks. Intracranial stenting with off-label balloon mounted coronary stents (BMCS) may be a viable alternative for patients with symptomatic intracranial stenosis who fail best medical therapy. Between December 2005 and June 2012, 42 symptomatic intracranial stenoses were treated with a BMCS after failing medical management. Procedural records, clinical outcomes, and imaging follow-up were reviewed. Outcome measurements included technical success rate, morbidity and mortality, long term stent patency, and clinical outcomes, as measured by the modified Rankin Scale. The technical success rate was 98% (41 of 42 lesions). Morbidity within the first 30 days was 7.1% (three of 42 lesions). Overall morbidity, including both periprocedural and long term evaluation, was 9.5% (four of 42 lesions). There were no deaths. Follow-up imaging was available for 30 stents (71%) with an average follow-up time of 35.1 months. Restenosis (>50%) and retreatment were observed in 20% and 10% of cases, respectively. Clinical evaluation by a neurologist ≥ 30 days postprocedure was available in 40 of 42 cases (95%) with an average of 32.1 months. At presentation, 55% of patients had a modified Rankin Scale (mRS) score of ≤ 2. At follow-up, 74% of patients were found to have an mRS score of ≤ 2. This study suggests that BMCS may benefit patients with symptomatic intracranial stenosis who experience stroke or transient ischemic attack in spite of best medical therapy.


Spacecraft bacterium, Paenibacillus pasadenensis, causing wound infection in humans.
In a patient with mediastinitis after cardiac surgery Paenibacillus pasadenensis was detected in his sternal wound. Paenibacilli are gram-positive, aerobic, bacteria related to bacilli. Until recently these organisms were not known to cause human disease. A few cases of human infection caused by another member of this genus, P alvei, have been reported. The authors describe the first infection with P pasadenensis in humans. P pasadenensis was detected by broad-range bacterial 16S rRNA PCR. Treatment consisted of surgical debridement and antibiotics, vancomycin and ciprofloxacin followed by clindamycin and ciprofloxacin, resulting in complete recovery.


Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis.
Noninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniques for some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formal assessment of performance. To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance. Systematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language human studies reporting primary data. References from review articles were also searched. Abstracts were read independently to identify studies reporting primary data suitable for analysis. Covariates included publication year, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extracted by 2 reviewers. From 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) were analyzed. Overall performance of the test to detect Y chromosome sequences had the following characteristics: sensitivity, 95.4% (95% confidence interval [CI], 94.7%-96.1%) and specificity, 98.6% (95% CI, 98.1%-99.0%); diagnostic odds ratio (OR), 885; positive predictive value, 98.8%; negative predictive value, 94.8%; area under curve (AUC), 0.993 (95% CI, 0.989-0.995), with significant interstudy heterogeneity. DNA methodology and gestational age had the largest effects on test performance. Methodology test characteristics were AUC, 0.988 (95% CI, 0.979-0.993) for polymerase chain reaction (PCR) and AUC, 0.996 (95% CI, 0.993-0.998) for real-time quantitative PCR (RTQ-PCR) (P = .02). Gestational age test characteristics were AUC, 0.989 (95% CI, 0.965-0.998) (<7 weeks); AUC, 0.994 (95% CI, 0.987-0.997) (7-12 weeks); AUC, 0.992 (95% CI, 0.983-0.996) (13-20 weeks); and AUC, 0.998 (95% CI, 0.990-0.999) (>20 weeks) (P = .02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (sensitivity, 96.0%; specificity, 99.0%) outperformed conventional PCR (sensitivity, 94.0%; specificity, 97.3%). Testing after 20 weeks (sensitivity, 99.0%; specificity, 99.6%) outperformed testing prior to 7 weeks (sensitivity, 74.5%; specificity, 99.1%), testing at 7 through 12 weeks (sensitivity, 94.8%; specificity, 98.9%), and 13 through 20 weeks (sensitivity, 95.5%; specificity, 99.1%). Despite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Y chromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7 weeks' gestation were unreliable.


The Impact of Immunomodulatory Treatment on Kappa Free Light Chains as Biomarker in Neuroinflammation.
Kappa free light chains (KFLC) are a promising new biomarker to detect neuroinflammation. Still, the impact of pre-analytical effects on KFLC concentrations was not investigated. KFLC concentrations were measured in serum and cerebrospinal fluid (CSF) of patients with a newly diagnosed multiple sclerosis (MS) or clinically isolated syndrome (CIS) before (n = 42) or after therapy with high-dose methylprednisolone (n = 65). In prospective experiments, KFLC concentrations were analyzed in the same patients in serum before and after treatment with high-dose methylprednisolone (n = 16), plasma exchange (n = 12), immunoadsorption (n = 10), or intravenous immunoglobulins (n = 10). In addition, the influence of storage time, sample method, and contamination of CSF with blood were investigated. Patients diagnosed with MS/CIS and treated with methylprednisolone showed significantly lower KFLC concentrations in serum as untreated patients. Repeated longitudinal investigations revealed that serum KFLC concentrations continuously decreased after each application of methylprednisolone. In contrast, other immune therapies and further pre-analytical conditions did not influence KFLC concentrations. Our results show prominent effects of steroids on KFLC concentrations. In contrast, various other pre-analytical conditions did not influence KFLC concentrations, indicating the stability of this biomarker.


Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study.
Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus control). In-hospital pain scores and side effects were not different between groups. In the 30 days after discharge, patients who received methadone 0.15 mg/kg had less pain at rest (P = .02) and used fewer opioid pills than controls (P < .0001), whereas patients who received 0.1 mg/kg had no difference in pain at rest (P = .69) and opioid use compared to controls (P = .08). In same-day discharge surgery, this pilot study identified a single intraoperative dose of methadone (0.15 mg/kg ideal body weight), which decreased intraoperative and postoperative opioid requirements and postoperative pain, compared with conventional intermittent short-duration opioids, with similar side effects.


Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding.
Zinc noncompetitively antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in cultured neurons. We investigated the mechanism of this inhibition by examining the effect of zinc on ligand binding to three distinct sites on the NMDA receptor in rat hippocampal membranes. Zinc dose-dependently inhibited both the association and dissociation of the NMDA channel blocker [3H]N-(1-[thienyl]cyclohexyl)piperidine ([3H]TCP) but had no effect on steady state levels of [3H]TCP binding. This suggests that zinc inhibits the receptor-gated access of [3H]TCP to its site in the ion channel but has no effect on the binding site itself. Zinc inhibition of [3H]TCP association was not mediated by an action at the NMDA recognition site, because zinc had no effect on NMDA-displaceable L-[3H]glutamate binding. On the other hand, zinc dose-dependently inhibited [3H]glycine binding by a noncompetitive interaction. Stoichiometric analysis of equilibrium binding data indicated the presence of two [3H]glycine binding sites/[3H]TCP binding site. Comparison of the potencies of zinc in inhibiting glycine-dependent [3H]TCP association and [3H]glycine binding suggests that blockade of only one of the two glycine sites is sufficient to prevent [3H]TCP association. We hypothesize that synaptically released zinc inhibits NMDA receptor-mediated responses by binding to a site on the receptor/channel complex, reducing glycine binding, and thereby decreasing what would otherwise be a tonically present action of endogenous extracellular glycine.


Case report of a transfusion-associated hepatitis A infection.
Documented transfusion-associated hepatitis A (TAHA) is rare, and blood donors in the United States are not routinely screened for this infection. We report a case of TAHA associated with a donation made 8 days after a donor returned from a trip to South America. This is a review of donor and recipient records and a review of the literature. A donor developed symptoms of hepatitis 20 days after donation (28 days after returning from South America). The donor reported the illness 56 days after donation when contacted to schedule another visit. By this time, the red blood cell and frozen plasma components had been transfused. The recipient of the plasma, a 15-month-old female, tested positive for immunoglobulin M antibody to hepatitis A virus 43 days after transfusion. The recipient had displayed mild, nonspecific symptoms approximately 2 weeks after transfusion. Hospital infection control investigated the potential for further spread within the hospital because the recipient had been an inpatient for most of the posttransfusion period. The risk of transmission to other patients was determined to be negligible because the patient had been in isolation for other reasons. Family members, who included a health care professional, were counseled and offered prophylaxis. TAHA may be underrecognized. This case was identified only because of a donor report at the time of recruitment. Asymptomatic donor viremia has been documented in plasma donors. Although TAHA rarely results in severe disease, the risk it creates of secondary transmission especially within the hospital setting is not inconsequential.


Antitumor effects of cationic synthetic peptides derived from Lys49 phospholipase A2 homologues of snake venoms.
The effects of two cationic synthetic peptides, derived from the C-terminal region of Lys49 phospholipase A2 homologues from snake venoms, upon various murine tumor cell lines (B16 melanoma, EMT6 mammary carcinoma, S-180 sarcoma, P3X myeloma, tEnd endothelial cells) were evaluated. The peptides are 13-mers derived from Agkistrodon piscivorus piscivorus Lys49 PLA2 (p-AppK: KKYKAYFKLKCKK) and Bothrops asper Lys49 myotoxin II (pEM-2[D]: KKWRWWLKALAKK), respectively, in the latter case with slight modifications and with all-D amino acids. All tumor cells tested were susceptible to the lytic action of the peptides. The susceptibility of tumor cell lines was not higher than that of C2C12 skeletal muscle myoblasts, utilized as a non-transformed cell line control. However, in a murine model of subcutaneous solid tumor growth of EMT6 mammary carcinoma, the intraperitoneal administration of pEM-2[D] caused a tumor mass reduction of 36% (p<0.05), which was of similar magnitude to that achieved by the administration of paclitaxel, an antitumor drug in clinical use. Thus, the C-terminal peptides of Lys49 phospholipase A2 homologues present antitumor effects that might be of interest in developing therapeutic strategies against cancer.


Polarization of specular reflection and near-specular scattering by a rough surface.
Polarization of specular reflection and near-specular scattering (NSS) by a randomly rough surface is investigated by the use of a Mueller matrix formulation. The collective effect by a rough surface on the average specular field results in reflectance loss and polarization, which can be explained by an effective medium theory. Effects of random NSS can be represented by a scattering matrix that is partially coherent and polarized. The incoherent and unpolarized part of scattering causes depolarization, and the coherent and polarized parts of scattering change the apparent polarization properties of specular reflection. Results of a simulation and least-squares fit of ellipsometric data to the models including the NSS effect, for a black anodized aluminum sample, are presented. Simultaneous least-squares fits for both ellipsometric data and reflectance data at multiple angles of incidence at three different wavelengths gave approximately the same rms roughness, which agrees with the profilometric values reported previously.


Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis.
Fibroblast Growth Factor-23 (FGF23) and cofactor Klotho are key regulators of mineral metabolism in chronic kidney disease (CKD), but little is known about the mechanisms that regulate their production. This study evaluates longitudinal changes of FGF23 and Klotho levels and their regulatory factors in children on chronic peritoneal dialysis (PD). FGF23, Klotho, 25(OH) vitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) plasma concentrations were measured during 1 year of follow-up in PD children. Anthropometric and dialytical parameters were evaluated in addition to mineral metabolism variables. Thirty-one patients under chronic PD were followed for 12 months. FGF23 mean plasma levels at Month 1 were significantly increased compared with controls, 215.1 ± 303.6 versus 9.4 ± 5.7 pg/mL, respectively (P < 0.001). Baseline Klotho levels were 41% lower in patients compared with controls, 132.1 ± 58 versus 320 ± 119.4 pg/mL, respectively (P < 0.001), and did not correlate with FGF23 and phosphorus levels. At Month 12, FGF23 (195 ± 300 pg/mL) and Klotho levels (130 ± 34 pg/mL) remained similar to baseline values. Log-FGF23 correlated significantly with height/age Z score (r= -0.38) and residual renal function (r = -0.44), but no correlation was found with serum phosphorus, phosphate intake, PTH and vitamin D levels. The log-FGF23 strongly correlated with calcium levels at Months 1, 6 and 12, however, this relationship was blunted if serum phosphorus was >6 mg/dL. By multiple regression analysis, calcium was the strongest variable determining FGF23 levels. In this longitudinal study, FGF23 levels are markedly increased, and Klotho levels are reduced in PD children compared with controls. FGF23 levels appeared to be regulated primarily by serum calcium, showing a significant correlation at each time of measurement. This relationship was lost in patients with phosphorus >6 mg/dL. These observations may have important consequences to the therapeutic management of phosphate homeostasis in CKD patients.


A distinct Bemisia tabaci (Gennadius) (Hemiptera: Sternorrhyncha: Aleyrodidae) genotype cluster is associated with the epidemic of severe cassava mosaic virus disease in Uganda.
During the 1990s, an epidemic of cassava mosaic virus disease caused major losses to cassava production in Uganda. Two factors associated with the epidemic were the occurrence of a novel recombinant begomovirus, EACMV-Ug, and unusually high populations of the whitefly vector, Bemisia tabaci. Here we present molecular evidence for the occurrence of two cassava-colonizing B. tabaci genotype clusters, Ug1 and Ug2, one of which, Ug2, can be consistently associated with the CMD epidemic in Uganda at the time of collection in 1997. By contrast, a second genotype cluster, Ug1, only occurred 'at' or 'ahead of' the epidemic 'front', sometimes in mixtures with Ug2. Comparison of mitochondrial cytochrome oxidase I gene sequences for Ug1 and Ug2 and well-studied B. tabaci reference populations indicated that the two Ugandan populations exhibited approximately 8% divergence, suggesting they represent distinct sub-Saharan African lineages. Neither Ugandan genotype cluster was identified as the widely distributed, polyphagous, and highly fecund B biotype of Old World origin, with which they both diverged by approximately 8%. Within genotype cluster divergence of Ug1 at 0.61 +/- 0.1% was twice that of Ug2 at 0.35 +/- 0.1%. Mismatch analysis suggested that Ug2 has undergone a recent population expansion and may be of nonUgandan origin, whereas Ug1 has diverged more slowly, and is likely to be an indigenous genotype cluster.


The Mechanism of Ligamentum Flavum Hypertrophy: Introducing Angiogenesis as a Critical Link That Couples Mechanical Stress and Hypertrophy.
Biochemical alterations associated with mechanical stress have been explored as an initiating step in the pathological progression of ligamentum flavum hypertrophy (LFH); however, this mechanism remains poorly understood. Recently, the inflammation induced after mechanical stress and the subsequent response of ligamentum flavum (LF) cells have been implicated in LFH pathology. To investigate the hypothesis that angiogenesis may be a critical link between hypertrophy and a series of stimulating events, including mechanical stress. LF from 20 lumbar spinal canal stenosis (LSCS) patients and 16 non-LSCS patients (control group) were collected during surgery. Patient demographic and radiographic data were obtained. The levels of angiogenic factors (vascular endothelial growth factor [VEGF], angiopoietin-1, vascular cell adhesion molecule, and basic fibroblast growth factor) in the LF were investigated by using an enzyme-linked immunosorbent assay. Angiogenesis was also quantified by immunohistochemical detection of CD34-positive capillaries. The correlations among clinical factors, including radiographic factors, angiogenic factors, and angiogenesis, were statistically analyzed. The LSCS group was older and exhibited a longer symptom duration, wider segmental motion, and thicker LF than the control group. The LSCS group showed significantly higher tissue concentrations of VEGF (P < .001) that positively correlated with LF thickness (r = 0.557, P < .001) and segmental motion (r = 0.586, P < .001). The LSCS group showed significantly more CD34-positive capillaries than the control group (P = .004). The LSCS group showed greater segmental motion, higher VEGF concentrations, and more CD34-positive capillaries than the control group. These data indicate that VEGF-mediated angiogenesis following mechanical stress may be a critical step within the series of pathological events in LFH.


Quality of Life after Salivary Gland Surgery.
Quality of life (QoL) has been recognized as an important endpoint in addition to disease-related and global survival. It is particularly important for patients with salivary gland neoplastic disease. For patients who are undergoing benign salivary gland tumor surgery, cosmetic and functional outcomes are extremely important, as these patients' psychological well-being and ability to function in society can be severely impacted. The following issues related to surgical treatment are discussed: incision, loss of local tissue sensation, development of Frey's syndrome, facial nerve function, and cosmesis. Improvements in the placement of the incision combined with additional minimally invasive procedures have improved QoL. The ultimate goal of benign parotid neoplastic surgery is complete tumor excision while avoiding cosmetic and functional damage, which includes preservation of the function of the facial nerve and its branches; this is the key to maintaining preoperative levels of QoL. There are many measures available to improve cosmesis that have minimal morbidity and that, when used, can provide significant improvements in patient outcomes. The treatment of malignant salivary gland neoplasms is primarily directed at treating the malignancy. When surgical treatment affects important neighboring structures, such as the lingual or hypoglossal nerves, as in submandibular/sublingual cancer, there is a tremendous effect on QoL if postoperative dysfunction of these structures results. Often, this treatment involves using ancillary surgical procedures, such as neck dissection, or nonsurgical treatment, such as radiation therapy. The effect of such multi-modality treatment on QoL is significant. The treatment of underlying salivary disease is often overshadowed by these adjunctive treatments.


Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription.
The Akt (or protein kinase B) and Cot (or Tpl-2) serine/threonine kinases are associated with cellular transformation. These kinases have also been implicated in the induction of NF-kappa B-dependent transcription. As a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, Cot can also activate MAP kinase signaling pathways that target AP-1 and NFAT family transcription factors. Here we show that Akt and Cot physically associate and functionally cooperate. Akt appears to function upstream of Cot, as Akt can enhance Cot induction of NF-kappa B-dependent transcription, and dominant-negative Cot blocks the activation of this element by Akt. Furthermore, deletion analysis shows that binding to Akt is critical for Cot function. The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400), near the carboxy terminus of Cot. However, phosphorylation at this site is not required for Cot kinase activity or AP-1 induction, suggesting it specifically regulates Cot effector function at the level of the NF-kappa B pathway. Mutation of S400 in Cot does indeed abolish its ability to activate I kappa B-kinase (IKK) complexes, but paradoxically it allows for increased Cot association with the IKK complex. This mutated form of Cot also acts as a dominant negative for T-cell antigen receptor/CD28- or Akt/phorbol myristate acetate-induced NF-kappa B induction, while having relatively little effect on tumor necrosis factor induction of NF-kappa B. These findings suggest that the activation of different signaling pathways by MAP3Ks may be regulated separately and may provide evidence for how such discrimination by one member of this kinase family occurs.


The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta.
Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responses to aversive stimuli. We now designate the region containing them as the "mesopontine rostromedial tegmental nucleus" (RMTg) and report herein on its neuroanatomy. Dense micro-opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial, and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic-lateral hypothalamic continuum, and midline-intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe, and locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures.


Molecular cloning, expression, and characterization of a Ca2+-dependent, membrane-associated nuclease of Mycoplasma genitalium.
In this study, we identified and characterized the enzymatic properties of MG_186, a calcium-dependent Mycoplasma genitalium nuclease. MG_186 displays the hallmarks of nucleases, as indicated by its amino acid sequence similarity to other nucleases. We cloned, UGA corrected, expressed, purified, and demonstrated that recombinant MG_186 (rMG_186) exhibits nuclease activity similar to that of typical sugar-nonspecific endonucleases and exonucleases. Biochemical characterization indicated that Ca2+ alone enhances its activity, which was inhibited by divalent cations, such as Zn2+ and Mn2+. Chelating agents EGTA and EDTA also inhibited nuclease activity. Mycoplasma membrane fractionation and Triton X-114 phase separation showed that MG_186 was a membrane-associated lipoprotein, and electron microscopy revealed its surface membrane location. Incubation of purified human endometrial cell nuclei with rMG_186 resulted in DNA degradation and morphological changes typical of apoptosis. Further, immunofluorescence analysis of rMG_186-treated nuclei indicated that morphological changes were linked to the disintegration of lamin and the internalization of rMG_186. Since M. genitalium has the capacity to invade eukaryotic cells and localize to the perinuclear and nuclear region of parasitized target cells, MG_186 has the potential to provide M. genitalium, which possesses the smallest genome of any self-replicating cell, with the ability to degrade host nucleic acids both as a source of nucleotide precursors for growth and for pathogenic purposes.


Annoyance caused by the sounds of a magnetic levitation train.
In a laboratory study, the annoyance caused by the passby sounds from a magnetic levitation (maglev) train was investigated. The listeners were presented with various sound fragments. The task of the listeners was to respond after each presentation to the question: "How annoying would you find the sound in the preceding period if you were exposed to it at home on a regular basis?" The independent variables were (a) the driving speed of the maglev train (varying from 100 to 400 km/h), (b) the outdoor A-weighted sound exposure level (ASEL) of the passbys (varying from 65 to 90 dB), and (c) the simulated outdoor-to-indoor reduction in sound level (windows open or windows closed). As references to the passby sounds from the maglev train (type Transrapid 08), sounds from road traffic (passenger cars and trucks) and more conventional railway (intercity trains) were included for rating also. Four important results were obtained. Provided that the outdoor ASELs were the same, (1) the annoyance was independent of the driving speed of the maglev train, (2) the annoyance caused by the maglev train was considerably higher than that caused by the intercity train, (3) the annoyance caused by the maglev train was hardly different from that caused by road traffic, and (4) the results (1)-(3) held true both for open or closed windows. On the basis of the present results, it might be expected that the sounds are equally annoying if the ASELs of the maglev-train passbys are at least 5 dB lower than those of the intercity train passbys. Consequently, the results of the present experiment do not support application of a railway bonus to the maglev-train sounds.


Primary Leiomyosarcoma of the Mesentery: A Case Report.
Mesenteric masses are infrequent lesions ranging from benign cysts to aggressive malignancies and often present a diagnostic and therapeutic challenge. The mesentery is a frequent recipient of metastases from the gastrointestinal tract, pancreas, and biliary cancers. Primary mesenteric tumors are relatively rare, mostly mesenchymal in origin and benign in nature. Examples include gastrointestinal stromal tumors and smooth muscle tumors. We describe a 50-year-old woman, who presented with a lump in the left hypochondrium along with altered bowel habits of 2 years' duration. Imaging revealed a cystic lesion, raising the differentials of a benign lesion. Exploratory laparotomy revealed a large cystic mass in the mesentery closely abutting the jejunal loops. This was followed by mass resection along with a segment of the jejunum. Histopathological examination revealed features of a leiomyosarcoma. Postoperatively, the patient developed a colocutaneous fistula, which was re-excised. At 6 months' follow-up, the patient is doing well. Our case demonstrates the diagnostic challenge posed by the atypical clinical and imaging features of this tumor at an unusual site.


Statistical dependence of clinical data on the chosen treatment of patients with a multivessel coronary artery disease.
In this study we tried to check which clinical data are connected with the choice of treatment in patients with a multivessel coronary artery disease. The data of 137 patients with a multivessel coronary artery disease, were analysed retrospectively. The patients were divided into three groups: treated conservatively, CABG and PTCA. Multivessel coronary artery disease was recognised when there were atherosclerotic changes in more a 2 vessels with a not less a 2 mm in diameter. Patients with previous CABG or a left main coronary artery disease were excluded. The data were analysed by means of several methods, variance analysis, correlation analysis, discriminant functions, chi-square test and T-Student test. For treatment decision making in multivessel coronary artery disease of statistical significance were: the state of the left anterior descendent artery below the first diagonal branch, the state of the first diagonal branch and peripheral parts of the left anterior descendent artery and right coronary artery, the systolic function of the antero-lateral, apical and phrenic segments of the left ventricle, the global left ventricular ejection fraction in angiography and echocardiography, local systolic disturbances of the left ventricular observed in echocardiography, the coexistence of symptoms of heart failure as well as unstable angina. Treatment decision making will always depend not only on diagnostic procedures but also on all the clinical data about the patient and the experience of coworking cardiology and surgery centres.


Changing physician prescribing behaviour.
Didactic approaches to educating physicians and/or other health professionals do not produce changes in learner behaviour. Similarly, printed materials and practice guidelines have not been shown to change prescribing behaviour. Evidence-based educational approaches that do have an impact on provider behaviour include: teaching aimed at identified learning needs; interactive educational activities; sequenced and multifaceted interventions; enabling tools such as patient education programs, flow charts, and reminders; educational outreach or academic detailing; and audit and feedback to prescribers. Dr. Jean Gray reflects over the past 25 years on how there has been a transformation in the types of activities employed to improve prescribing practices in Nova Scotia. The evolution of Continuing Medical Education (CME) has resulted in the creation of the Drug Evaluation Alliance of Nova Scotia (DEANS) program, which is one exemplar of an evidence-based educational approach to improving physician prescribing in that province. Key words: Evidence-based, education, prescribing.


Phenylketonuria Scientific Review Conference: state of the science and future research needs.
New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.


Fluorescent carbocyanine dyes allow living neurons of identified origin to be studied in long-term cultures.
A prerequisite for many studies of neurons in culture is a means of determining their original identity. We needed such a technique to study the interactions in vitro between a class of spinal cord neurons, sympathetic preganglionic neurons, and their normal target, neurons from the sympathetic chain. Here, we describe how we use two highly fluorescent carbocyanine dyes, which differ in color but are otherwise similar, to identify neurons in culture. The long carbon chain carbocyanine dyes we use are lipid-soluble and so become incorporated into the plasma membrane. Neurons can be labeled either retrogradely or during dissociation. Some of the labeled membrane gradually becomes internalized and retains its fluorescence, allowing identification of cells for several weeks in culture. These dyes do not affect the survival, development, or basic physiological properties of neurons and do not spread detectably from labeled to unlabeled neurons. It seems likely that cells become retrogradely labeled mainly by lateral diffusion of dye in the plane of the membrane. If so, carbocyanine dyes may be most useful for retrograde labeling over relatively short distances. An additional feature of carbocyanine labeling is that neuronal processes are brightly fluorescent for the first few days in culture, presumably because dye rapidly diffuses into newly inserted membrane. We have used carbocyanine dyes to identify sympathetic preganglionic neurons in culture. Our results indicate that preganglionic neurons can survive in the absence of their target cells and that several aspects of their differentiation in the absence of target appear normal.


Isolation and characterization of the Escherichia coli htrB gene, whose product is essential for bacterial viability above 33 degrees C in rich media.
We have identified and studied the htrB gene of Escherichia coli. Insertional inactivation of the htrB gene leads to bacterial death at temperatures above 33 degrees C. The mutant bacterial phenotype at nonpermissive temperatures includes an arrest of cell division followed by the formation of bulges or filaments. The htrB+ gene has been cloned by complementation and shown to reside at 23.4 min on the E. coli genetic map, the relative order of the neighboring loci being mboA-htrB-pyrC. The htrB gene is transcribed in a counterclockwise fashion, relative to the E. coli genetic map, and its product has been identified as a membrane-associated protein of 35,000 Da. Growth experiments in minimal media indicate that the HtrB function becomes dispensable at low growth rates.


Biochemical evidence of sympathetic hyperactivity in human hypertension.
Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge), we noted a preferential activation of the cardiac sympathetic outflow; however, in fainting reactions ("vasovagal syncope"), which occur infrequently during the course of central venous catheter placement under local anesthesia, the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients), a differentiated activation of the sympathetic outflow to the heart and kidneys is present, based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade, brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study, we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects, suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.


Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers.
The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.


Comparative study of conservative and surgical management for symptomatic moderate and severe hydronephrosis in pregnancy: a prospective randomized study.
To analyze the role of different measures in the treatment of acute moderate or severe symptomatic hydronephrosis in pregnancy. Of the 18,130 women delivering at our institution between January 2000 and December 2004, 93 patients were admitted due to symptomatic hydronephrosis. Among these, 50 patients were diagnosed with moderate or severe hydronephrosis, and were randomly treated with conservative measures (25 patients) or double pigtail stent insertion (25 patients). Renal sonography, urinalysis, serum creatinine levels, white blood cell counts, and urine culture were done in all patients at first visit. The clinical and perinatal outcomes of the two groups were compared. The incidence of symptomatic hydronephrosis in pregnancy was 0.5% in our institution (93/18,130). The majority of the moderate or severe hydronephrosis (88%) cases were diagnosed after the first trimester. There were no statistically significant differences in the fetal body weight, Apgar score, preterm labor, and hospitalization day between the two groups. Among those receiving conservative treatment, five patients (5/25, 20%) failed to respond and were subsequently treated by double pigtail stent insertion successfully, compared with the surgical group, in which all patients were successfully relieved by double pigtail stent (p=0.018). Four patients receiving double pigtail stent insertion complained of stent discomfort and flank pain after the procedure (16%). Double pigtail stent insertion is effective for the treatment of moderate or severe symptomatic hydronephrosis in pregnancy, and showed a lower failure rate than the conservative treatment. However, due to the complications and discomfort with surgical treatment, conservative treatment should still be the first choice.


Structural and mechanistic implications of metal binding in the small heat-shock protein αB-crystallin.
The human small heat-shock protein αB-crystallin (αB) rescues misfolded proteins from irreversible aggregation during cellular stress. Binding of Cu(II) was shown to modulate the oligomeric architecture and the chaperone activity of αB. However, the mechanistic basis of this stimulation is so far not understood. We provide here first structural insights into this Cu(II)-mediated modulation of chaperone function using NMR spectroscopy and other biophysical approaches. We show that the α-crystallin domain is the elementary Cu(II)-binding unit specifically coordinating one Cu(II) ion with picomolar binding affinity. Putative Cu(II) ligands are His(83), His(104), His(111), and Asp(109) at the dimer interface. These loop residues are conserved among different metazoans, but also for human αA-crystallin, HSP20, and HSP27. The involvement of Asp(109) has direct implications for dimer stability, because this residue forms a salt bridge with the disease-related Arg(120) of the neighboring monomer. Furthermore, we observe structural reorganization of strands β2-β3 triggered by Cu(II) binding. This N-terminal region is known to mediate both the intermolecular arrangement in αB oligomers and the binding of client proteins. In the presence of Cu(II), the size and the heterogeneity of αB multimers are increased. At the same time, Cu(II) increases the chaperone activity of αB toward the lens-specific protein β(L)-crystallin. We therefore suggest that Cu(II) binding unblocks potential client binding sites and alters quaternary dynamics of both the dimeric building block as well as the higher order assemblies of αB.


Image cytometry: protocols for 2D and 3D quantification in microscopic images.
Microscopy-based imaging is booming and the need for tools to retrieve quantitative data from images is urgent. This book provides simple but reliable tools to generate valid quantitative gene expression data, at the mRNA, protein and activity level, from microscopic images in relation to structures in cells, tissues and organs in 2D and 3D. Volumes, areas, lengths and numbers of cells and tissues can be calculated and related to these gene expression data while preserving the 2D and 3D morphology. Image cytometry thus provides a comprehensive toolkit to study molecular processes and structural changes at the level of cells and tissues.


Home-based evaluation of executive function (Home-MET) for older adults with mild cognitive impairment.
Executive function helps older adults maintain their activities of daily living by making plans, setting goals, and carrying them out successfully. It is important for their independence in community living. With a carefully match-group of 80 mild cognitive impaired with 80 health control subjects. The home-based evaluation of executive function (Home-MET) was validated in subjects' own living environment. This Home-MET showed significant correlation in the assessment of attention control that was assessing by Test of Everyday Attention (TEA) (r = .86, p < .01), with working memory that was assessed with Trail Making Test (TMT) (r = .72, p < .01), with inhibitory control that was assessing with Stroop Test (r = .86, p < .01), with individuals' functional disability was assessed by Chinese Disability Assessment of Dementia (CDAD) (r = .77, p < .01) and cognitive assessment was assessed by Hong Kong Montreal Cognitive Assessment (HK-MoCA) (r = .88, p < .01). By benchmarking with the validated performance-based executive function assessment, the Home-MET shows significant correlation (r = .92, p < .05) with the executive function test in a standard environment in hospital, i.e. the Chinese Multiple Errands Test (the Chinese-MET). The two-stage hierarchical linear regression model with backward method showed functional disability was a marginally significant predictor (p < .059) for the Home-MET with regression model showed with R2 = .93. Results indicated the Home-MET, can provide an objective measure of executive function for subjects with mild cognitive impairment in participants' own home environment.


Cretaceous winged stick insects clarify the early evolution of Phasmatodea.
Wingless and shorter winged stick insects are very common today, but most known extinct stick insects had fully developed wings, leading to contentious affinities among the extinct winged and extant groups. We report herein three male winged stick insects, assigned to Pterophasmatidae fam. nov., from mid-Cretaceous Myanmar (Burmese) amber. Pterophasmatidae fam. nov. are regarded as transitional taxa from extinct winged to modern wingless and shorter winged stick insects based on their similar tegmina venation with extinct Susumanioidea and some body features the same as extant Phasmatodea. However, their symmetric phallic organs comprising two consistent phallomeres are different from those of all living groups. Phylogenetic analyses suggest that the extinct winged taxa, including the new family, are the stem groups of modern stick and leaf insects, and all of them constitute the clade of Phasmatodea. New findings indicate winged and wingless stick insects' morphologies diversified significantly during or before the mid-Cretaceous.


Evaluation of gravid traps for the collection of Culex quinquefasciatus, a vector of lymphatic filariasis in Tanzania.
Although several studies have suggested that gravid traps might be useful for collection of mosquitoes, particularly Culex quinquefasciatus, to monitor transmission of the nematode Wuchereria bancrofti (xenomonitoring), there has not been a study to see which of the currently available gravid traps is most effective in endemic areas. The present study evaluated the comparative efficacy for collection of Cx quinquefasciatus of four commercially available gravid traps: the CDC, Frommer Updraft, Reiter-Cummings and Harris County traps. Trap evaluations were conducted in two locations in Tanzania, Ifakara and Tanga. Mosquitoes collected were identified to species, sex, and gonotrophic status. In both locations, the CDC gravid trap collected the highest number of mosquitoes, the highest number of Cx quinquefasciatus, and the highest proportion of gravid mosquitoes. Although it damaged the highest proportion of mosquitoes as they passed through the trap fan, the CDC gravid trap also contained the highest number of living mosquitoes, when the traps were collected in the morning. The CDC gravid traps collected significantly more phlebotomine sandflies than the other traps and in Tanga, where they were more frequent, the highest number of biting midges. The effectiveness of all four gravid traps should encourage the sampling of Cx quinquefasciatus where it is an important disease vector or nuisance mosquito. The unexpected collection of phlebotomine sandflies and biting midges indicates that gravid traps might usefully collect other insects, including those of medical importance.


Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models.
Cancer cachexia is a syndrome that impairs the quality of life and overall survival of patients, and thus the effectiveness of anticancer agents. There are no effective therapies for cancer cachexia due to the complexity of the syndrome, and insufficient knowledge of its pathogenesis results in difficulty establishing appropriate animal models. Previously, promising results have been obtained in clinical trials using novel agents including the ghrelin receptor agonist anamorelin, and the selective androgen receptor modulator (SARM) enobosarm to treat cachexia in patients with cancer. The present study examined the pharmacological effects of SARM-2f, a novel non-steroidal small molecule SARM, in animal models. SARM-2f increased body and skeletal muscle weight without significantly increasing the weight of the seminal vesicles or prostates of the castrated male rats. In the mice with tumor necrosis factor α-induced cachexia, SARM-2f and TP restored body weight, carcass weight, and food consumption rate. In the C26 and G361 cancer cachexia animal models, body and carcass weight, lean body mass, and the weight of the levator ani muscle were increased by SARM-2f and TP treatments. Tissue selectivity of SARM-2f was also observed in these animal models. The results demonstrate the anabolic effects of SARM-2f in a cytokine-induced cachexia model and other cancer cachexia models, and suggest that SARM-2f may be a novel therapeutic option for cachexia in patients with cancer.


Experiments on torrefied wood pellet: study by gasification and characterization for waste biomass to energy applications.
Samples of torrefied wood pellet produced by low-temperature microwave pyrolysis were tested through a series of experiments relevant to present and near future waste to energy conversion technologies. Operational performance was assessed using a modern small-scale downdraft gasifier. Owing to the pellet's shape and surface hardness, excellent flow characteristics were observed. The torrefied pellet had a high energy density, and although a beneficial property, this highlighted the present inflexibility of downdraft gasifiers in respect of feedstock tolerance due to the inability to contain very high temperatures inside the reactor during operation. Analyses indicated that the torrefaction process had not significantly altered inherent kinetic properties to a great extent; however, both activation energy and pre-exponential factor were slightly higher than virgin biomass from which the pellet was derived. Thermogravimetric analysis-derived reaction kinetics (CO2 gasification), bomb calorimetry, proximate and ultimate analyses, and the Bond Work Index grindability test provided a more comprehensive characterization of the torrefied pellet's suitability as a fuel for gasification and also other combustion applications. It exhibited significant improvements in grindability energy demand and particle size control compared to other non-treated and thermally treated biomass pellets, along with a high calorific value, and excellent resistance to water.


Interleukin-6 and IgA-rheumatoid factor are crucial for baseline erosiveness, and anti-citrullinated peptide antibodies for radiographic progression in early rheumatoid arthritis treated according to a treat-to-target strategy.
To define baseline clinical and immunological characteristics [anti-citrullinated peptide antibodies (ACPAs), immunoglobulin M (IgM)- and IgA-rheumatoid factor (RF), and interleukin-6 (IL-6) levels] involved in determining baseline erosiveness, outcome, and radiographic progression among seropositive and seronegative early rheumatoid arthritis (ERA) patients. The 408 ERA patients enrolled in the study were monitored every 3 months according to the treat-to-target strategy. At baseline and after 12 months, hand and foot radiographs were evaluated using the Sharp/van der Heijde erosion score. At diagnosis, seronegative patients were older and had higher Disease Activity Scores (DASs) than seropositive patients. A higher risk of erosiveness at baseline was conferred by IgA-RF positivity and IL-6 plasma levels ≥7.6 pg/mL, particularly when simultaneously present. In multivariate analysis, disease duration and IL-6 plasma levels ≥7.6 pg/mL arose as independent variables associated with presence of erosions at onset. Radiographic progression at 1 year follow-up, which occurred in 11.1% of ERA patients, was predicted by ACPA positivity, together with higher age at diagnosis. Despite similar percentages of good European League Against Rheumatism response, DAS and Boolean remission being observed over time among seropositive and seronegative patients and between erosive and non-erosive subjects, ERA patients who were erosive at onset, IgA-RF seropositive, and simultaneously having high baseline IL-6 plasma levels (≥7.6 pg/mL) were treated to a greater extent with tumour necrosis factor blockers after 12 months. IgA-RF positivity and IL-6 plasma levels are crucial for baseline erosiveness, while ACPA positivity represents the strongest risk factor for developing radiographic progression in ERA.


Barriers to participation in web-based and in-person weight management interventions for serious mental illness.
This study examines barriers to participation and retention in 2 modalities (web-based and in-person) of a weight-management intervention tailored for individuals with serious mental illness (SMI). Using a mixed-methods approach, we explored the barriers veterans with SMI face when participating in a web-based (WebMOVE) or in-person (MOVE-SMI) version of the same SMI-adapted MOVE weight-management program. Participants in the randomized controlled trial (n = 277) were recruited from specialty mental health clinics at a Veterans Affairs medical center. Barriers were analyzed across treatment condition and program attendance (engagement) at baseline and follow-up using a generalized lineal model. Post hoc analyses assessed whether changes in the trajectory of barriers over time were associated with engagement. A subsample of participants (n = 48) from the WebMOVE and MOVE-SMI treatment conditions completed a qualitative interview, and 2 coders used open coding to analyze the data. Although barriers specific to treatment modality existed, most barriers cut across intervention modality, including financial hardship, lack of reliable housing and transportation, comorbid physical and mental health issues, and competing demands on personal time. Results of post hoc analyses found the association between engagement and emotional and motivational factors to be statistically significant. This study is the 1st to identify barriers in a web-based intervention for SMI. Similar barriers persisted across treatment modalities. Known barriers, particularly socioeconomic barriers, should be addressed to improve engagement and retention of individuals in weight-management interventions adapted for SMI, irrespective of modality. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Characterizing a collective and dynamic component of chromatin immunoprecipitation enrichment profiles in yeast.
Recent chromatin immunoprecipitation (ChIP) experiments in fly, mouse, and human have revealed the existence of high-occupancy target (HOT) regions or "hotspots" that show enrichment across many assayed DNA-binding proteins. Similar co-enrichment observed in yeast so far has been treated as artifactual, and has not been fully characterized. Here we reanalyze ChIP data from both array-based and sequencing-based experiments to show that in the yeast S. cerevisiae, the collective enrichment phenomenon is strongly associated with proximity to noncoding RNA genes and with nucleosome depletion. DNA sequence motifs that confer binding affinity for the proteins are largely absent from these hotspots, suggesting that protein-protein interactions play a prominent role. The hotspots are condition-specific, suggesting that they reflect a chromatin state or protein state, and are not a static feature of underlying sequence. Additionally, only a subset of all assayed factors is associated with these loci, suggesting that the co-enrichment cannot be simply explained by a chromatin state that is universally more prone to immunoprecipitation. Together our results suggest that the co-enrichment patterns observed in yeast represent transcription factor co-occupancy. More generally, they make clear that great caution must be used when interpreting ChIP enrichment profiles for individual factors in isolation, as they will include factor-specific as well as collective contributions.


Micronutrients in HIV: a Bayesian meta-analysis.
Approximately 28.5 million people living with HIV are eligible for treatment (CD4<500), but currently have no access to antiretroviral therapy. Reduced serum level of micronutrients is common in HIV disease. Micronutrient supplementation (MNS) may mitigate disease progression and mortality. We synthesized evidence on the effect of micronutrient supplementation on mortality and rate of disease progression in HIV disease. We searched MEDLINE, EMBASE, the Cochrane Central, AMED and CINAHL databases through December 2014, without language restriction, for studies of greater than 3 micronutrients versus any or no comparator. We built a hierarchical Bayesian random effects model to synthesize results. Inferences are based on the posterior distribution of the population effects; posterior distributions were approximated by Markov chain Monte Carlo in OpenBugs. From 2166 initial references, we selected 49 studies for full review and identified eight reporting on disease progression and/or mortality. Bayesian synthesis of data from 2,249 adults in three studies estimated the relative risk of disease progression in subjects on MNS vs. control as 0.62 (95% credible interval, 0.37, 0.96). Median number needed to treat is 8.4 (4.8, 29.9) and the Bayes Factor 53.4. Based on data reporting on 4,095 adults reporting mortality in 7 randomized controlled studies, the RR was 0.84 (0.38, 1.85), NNT is 25 (4.3, ∞). MNS significantly and substantially slows disease progression in HIV+ adults not on ARV, and possibly reduces mortality. Micronutrient supplements are effective in reducing progression with a posterior probability of 97.9%. Considering MNS low cost and lack of adverse effects, MNS should be standard of care for HIV+ adults not yet on ARV.


[The role of dermatosis on diabetes patient's quality of life].
It is known that diabetes mellitus (DM) motives the dermatosis cutaneous because of the proper affection, infections, medicine reactions or the diabetic foot. In this manner, the objective of this study is to work on the hypothesis and identify the influence of the dermatosis in the quality of life of the carrier of DM. It is an analytical, transversal and quantitative study, developed in the Family Health Program (PSF) at Odilom Lacerda, Planura, Minas Gerais State. The sample is composed by 47 (100%) patient carriers of DM, registered in the program called HIPERDIA. Data collection was done by a dermatologist, who applied anamnesis and a chart about the influence of the dermatosis in the quality of life during a medical consultation. The analysis of the data was numerical and percentile following the criteria: high frequency (80 to 100%), average frequency (50 to 79%), low frequency (1 to 49%) and null (for non-existent situations). All the patients of the study (47-100%) presented dermatosis and demonstrated its influence in quality of life, with average frequency for skin dryness and painful sensation in (24-51%); low frequency, especially the difficulty in the personal hygiene (19-40.3%) and the interference in the interpersonal relationship with relatives or friends (18-38.2%).


Assessment of wakefulness during awake craniotomy to predict intraoperative language performance.
Maximal safe tumor resection in language areas of the brain relies on a patient's ability to perform intraoperative language tasks. Assessing the performance of these tasks during awake craniotomies allows the neurosurgeon to identify and preserve brain regions that are critical for language processing. However, receiving sedation and analgesia just prior to experiencing an awake craniotomy may reduce a patient's wakefulness, leading to transient language and/or cognitive impairments that do not completely subside before language testing begins. At present, the degree to which wakefulness influences intraoperative language task performance is unclear. Therefore, the authors sought to determine whether any of 5 brief measures of wakefulness predicts such performance during awake craniotomies for glioma resection. The authors recruited 21 patients with dominant hemisphere low- and high-grade gliomas. Each patient performed baseline wakefulness measures in addition to picture-naming and text-reading language tasks 24 hours before undergoing an awake craniotomy. The patients performed these same tasks again in the operating room following the cessation of anesthesia medications. The authors then conducted statistical analyses to investigate potential relationships between wakefulness measures and language task performance. Relative to baseline, performance on 3 of the 4 objective wakefulness measures (rapid counting, button pressing, and vigilance) declined in the operating room. Moreover, these declines appeared in the complete absence of self-reported changes in arousal. Performance on language tasks similarly declined in the intraoperative setting, with patients experiencing greater declines in picture naming than in text reading. Finally, performance declines on rapid counting and vigilance wakefulness tasks predicted performance declines on the picture-naming task. Current subjective methods for assessing wakefulness during awake craniotomies may be insufficient. The administration of objective measures of wakefulness just prior to language task administration may help to ensure that patients are ready for testing. It may also allow neurosurgeons to identify patients who are at risk for poor intraoperative performance.


The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.


Right insular atrophy in neurocardiogenic syncope: a volumetric MRI study.
Alterations in the central autonomic network are hypothesized to play a role in the pathophysiologic mechanism underlying neurocardiogenic syncope; however, few data are available regarding the structural changes of the brain in this condition. We used voxel-based morphometry and regional volumetry to identify possible neuroanatomic correlates. We prospectively studied 32 patients with neurocardiogenic syncope with a positive response to the head-up tilt test and 32 controls who had no history of syncope. We used voxel-based morphometry to compare GM volumes between patients and controls. In addition, regional volumes of structures known to be included in the central autonomic network were measured and compared between the groups. Correlation analyses were also performed between clinical variables and anatomic data. Voxel-based morphometry showed a significant GM volume reduction in the right insular cortex in patients with neurocardiogenic syncope compared with controls (corrected P = .033). Regional volumetry showed a significant reduction of right insular volumes in patients compared with controls (P = .002, MANCOVA). Smaller right insular volumes in patients with neurocardiogenic syncope were related to larger drops in systolic (P = .020) and diastolic (P = .003) blood pressures during the head-up tilt test. We observed a novel finding of right insular atrophy in patients with neurocardiogenic syncope with a positive response to the head-up tilt test, implicating the role of right insular dysfunction in the pathophysiologic mechanism underlying neurocardiogenic syncope. Our findings further support the hypothesis that right insular dysfunction may cause a decrease in sympathetic activity and a reciprocal increase in parasympathetic activity, leading to syncope.


The Arabidopsis thaliana brassinosteroid receptor (AtBRI1) contains a domain that functions as a guanylyl cyclase in vitro.
Guanylyl cyclases (GCs) catalyze the formation of the second messenger guanosine 3',5'-cyclic monophosphate (cGMP) from guanosine 5'-triphosphate (GTP). Cyclic GMP has been implicated in an increasing number of plant processes, including responses to abiotic stresses such as dehydration and salt, as well as hormones. Here we used a rational search strategy based on conserved and functionally assigned residues in the catalytic centre of annotated GCs to identify candidate GCs in Arabidopsis thaliana and show that one of the candidates is the brassinosteroid receptor AtBR1, a leucine rich repeat receptor like kinase. We have cloned and expressed a 114 amino acid recombinant protein (AtBR1-GC) that harbours the putative catalytic domain, and demonstrate that this molecule can convert GTP to cGMP in vitro. Our results suggest that AtBR1 may belong to a novel class of GCs that contains both a cytosolic kinase and GC domain, and thus have a domain organisation that is not dissimilar to that of atrial natriuretic peptide receptors, NPR1 and NPR2. The findings also suggest that cGMP may have a role as a second messenger in brassinosteroid signalling. In addition, it is conceivable that other proteins containing the extended GC search motif may also have catalytic activity, thus implying that a significant number of GCs, both in plants and animals, remain to be discovered, and this is in keeping with the fact that the single cellular green alga Chlamydomonas reinhardtii contains over 90 annotated putative CGs.