Genetic Evidence of a Population Bottleneck and Inbreeding in the Endangered New Zealand Sea Lion, Phocarctos hookeri.
The New Zealand sea lion (NZSL) is of high conservation concern due to its limited distribution and its declining population size. Historically, it occupied most of coastal New Zealand, but is now restricted to a few coastal sites in southern mainland New Zealand and the sub-Antarctic Islands. NZSLs have experienced a recent reduction in population size due to sealing in the 1900s, which is expected to have resulted in increased inbreeding and a loss of genetic variation, potentially reducing the evolutionary capacity of the species and negatively impacting on its long-term prospects for survival. We used 17 microsatellite loci, previously shown to have cross-species applications in pinnipeds, to determine locus- and population-specific statistics for 1205 NZSLs from 7 consecutive breeding seasons. We show that the NZSL population has a moderate level of genetic diversity in comparison to other pinnipeds. We provide genetic evidence for a population reduction, likely caused by historical sealing, and a measure of allele sharing/parental relatedness (internal relatedness) that is suggestive of increased inbreeding in pups that died during recent epizootic episodes. We hypothesize that population bottlenecks and nonrandom mating have impacted on the population genetic architecture of NZSLs, affecting its population recovery.


The formation of choline O-sulphate by Pseudomonas C12B and other Pseudomonas species.
Pseudomonas C(12)B and other Pseudomonas species released larger amounts of a (35)S-labelled metabolite into the medium when cultured on growth-limiting concentrations of Na(2)SO(4) as opposed to growth in SO(4) (2-)-sufficient media. The metabolite was found at all stages of the culture cycle of Pseudomonas C(12)B and maximum quantities occurred in stationary-phase culture supernatants. The metabolite was not detected when the bacterium was cultured on growth-limiting concentrations of potassium phosphate. The amount of the metabolite present in the medium greatly exceeded that which could be extracted from intact cells and, except for choline chloride, it was independent of the carbon source used for growth. If choline chloride was present in high concentration, then larger amounts of the metabolite were found in the culture medium. The metabolite was not detected extracellularly or intracellularly when the bacterium was grown in SO(4) (2-)-deficient media containing 5mm-l-cysteine. The same metabolite was also synthesized in vitro only when Pseudomonas C(12)B extracts were incubated with choline chloride, ATP, MgCl(2) and Na(2) (35)SO(4). The metabolite-forming system was not subject to repression by Na(2)SO(4) and was completely inhibited by 0.5mm-l-cysteine and activated by Na(2)SO(4) (up to 1.0mm). The metabolite was identified as choline O-sulphate by electrophoresis, chromatography and isotope-dilution analysis. Another (35)S-labelled metabolite was also detected in culture supernatants, but was not identified.


Fetal translocation and metabolism of PAH obtained from coal fly ash given intratracheally to pregnant rats.
Polycyclic aromatic hydrocarbons (PAH) were extracted from coal fly ash collected from the electrostatic precipitator of a thermal power plant. The PAH extract was given intratracheally daily to pregnant rats (2 mg/100 g body weight) on d 18 and 19 of gestation. In addition on d 19 of gestation rats were also given [3H]benzo[a]pyrene intratracheally. Rats were sacrificed on d 20 of gestation, and the distribution of [3H]benzo[a]pyrene radioactivity and PAH of coal fly ash was studied in maternal lung, liver, and placenta, as well as in the liver and lung of the fetus. The radioactivity of intratracheally given benzo[a]pyrene was found in liver (68%), placenta (4%), fetal lung (1.9%), and fetal liver (1.4%) of maternal lung. Intratracheally administered PAH of coal fly ash were translocated to maternal liver and placenta, as well as to the liver and lung of the fetus. PAH of coal fly ash were also metabolized to several minor and major metabolites by maternal lung, liver, and placenta, as well as by the maternal fetal liver and lung. Some of the PAH metabolites in lung and liver were common; however, the major metabolite of liver, M-16, was different from the major metabolite M-16 of lung. The major PAH metabolite of placenta, M-5, and fetal liver, F-12, were common PAH metabolites. M-2 and M-6 of the placenta and F-5 and F-10 of the fetal lung were also common.


Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs.
Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 patients without cirrhosis were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%), and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56), and hepatic steatosis (aOR: 1.78) at the time of initial biopsy were marginally associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/L versus <25% values >100 U/L) were strongly associated with fibrosis progression. Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important noninvasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment.


Physical interaction between TBX5 and MEF2C is required for early heart development.
TBX5 is a transcription factor which plays important roles in the development of the heart and upper limbs. Mutations in this gene produce the inherited disorder Holt-Oram syndrome. Here, we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the alpha-cardiac myosin heavy chain (MYH6). Mutants of TBX5, TBX5G80R, and TBX5R279X that produce severe cardiac phenotypes impair the synergy. Using fluorescence resonance energy transfer, we demonstrate the interaction of TBX5 and MEF2C in living cells. We also show that they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter. Morpholino-mediated knockdowns of Tbx5 and Mef2c in zebrafish suggest that the genetic interaction of these proteins is not only required for MYH6 expression but also essential for the early stages of heart development and survival. This is the first report of a functional interaction between a T-box protein and a MADS box factor that may be crucial in cardiomyocyte differentiation.


Breast cancer risk after occupational solvent exposure: the influence of timing and setting.
Organic solvents are ubiquitous in occupational settings where they may contribute to risks for carcinogenesis. However, there is limited information on organic solvents as human breast carcinogens. We examined the relationship between occupational exposure to solvents and breast cancer in a prospective study of 47,661 women with an occupational history in the Sister Study cohort. Occupational solvent exposure was categorized using self-reported job-specific solvent use collected at baseline. Multivariable Cox regression analyses were used to assess breast cancer risk, adjusting for established breast cancer risk factors. A total of 1,798 women were diagnosed with breast cancer during follow-up, including 1,255 invasive cases. Overall the risk of invasive breast cancer was not associated with lifetime exposure to solvents [HR, 1.04; 95% confidence interval (CI), 0.88-1.24]. Parous women who worked with solvents before their first full-term birth had an increased risk of estrogen receptor-positive invasive breast cancer compared with women who never worked with solvents (HR, 1.39; 95% CI, 1.03-1.86). A significantly elevated risk for estrogen receptor-positive invasive breast cancer was associated with solvent exposure among clinical laboratory technologists and technicians (HR, 2.00; 95% CI, 1.07-3.73). Occupational exposure to solvents before first birth, a critical period of breast tissue differentiation, may result in increased vulnerability for breast cancer. Our findings suggest a need for future studies in this area to focus on exposure time windows and solvent types in different occupational settings.


Perforated sigmoid diverticulitis in a lumbar hernia after iliac crest bone graft--a case report.
The combination of perforated diverticulitis in a lumbar hernia constitutes an extremely rare condition. We report a case of a 66 year old Caucasian woman presenting with perforated sigmoid diverticulitis localized in a lumbar hernia following iliac crest bone graft performed 18 years ago. Emergency treatment consisted of laparoscopic peritoneal lavage. Elective sigmoid resection was scheduled four months later. At the same time a laparoscopic hernia repair with a biologic mesh graft was performed. This case shows a very seldom clinical presentation of lumbar hernia. Secondary colonic resection and concurrent hernia repair with a biologic implant have proven useful in treating this rare condition.


Radical prostatectomy for locally advanced and metastatic prostate cancer.
The management of advanced prostate cancer remains challenging. Traditionally, radical prostatectomy was discouraged in patients with locally advanced or node positive disease owing to the increased complication rate and treatment related morbidity. However, technical advances and refinements in surgical techniques have enabled the outcomes for patients with high risk prostate cancer to be improved. More recently, the concept of cytoreductive prostatectomy has been described where surgery (often Combined with an extended lymph node dissection) is performed in the setting of metastatic disease. Indirect evidence suggests an advantage using the cytoreductive approach. Hypothetical explanations for this observed benefit include decreased tumour burden, immune modulation, improved response to secondary treatment and avoidance of secondary complications attributable to local tumour growth. Nevertheless, prospective trials are required to investigate this further.


Comparison of Lymphovenous Shunt Methods in a Rat Model: Supermicrosurgical Lymphaticovenular Anastomosis versus Microsurgical Lymphaticovenous Implantation.
Lymphaticovenular anastomosis and lymphaticovenous implantation are the most popular lymphovenous shunt operations for the treatment of obstructive lymphedema. However, no study has been reported regarding direct comparison between lymphaticovenular anastomosis and lymphaticovenous implantation. This study aimed to compare postoperative patency of lymphaticovenular anastomosis and lymphaticovenous implantation using a rat model. Twelve Wistar rats were used for the study. The rats were randomized into the lymphaticovenular anastomosis group (n = 6) or the lymphaticovenous implantation group (n = 6). In the lymphaticovenular anastomosis group, the largest femoral lymphatic vessel was anastomosed to a similar-size vein in an end-to-end intima-to-intima coaptation manner, and the other lymphatics were ligated. In the lymphaticovenous implantation group, the femoral lymphatic vessel and surrounding tissue were inserted into the short saphenous vein with a telescopic anastomosis technique. Patency was evaluated intraoperatively and 1 week postoperatively with patent blue dye and indocyanine green lymphography. The mean diameters of the lymphatic vessels and the veins were 0.242 mm (range, 0.20 to 0.35 mm) and 0.471 mm (range, 0.30 to 0.75 mm), respectively. Intraoperative patency was 100 percent (six of six) in both groups (p = 1.000). Postoperative patency was significantly higher in the lymphaticovenular anastomosis group compared with the lymphaticovenous implantation group [100 percent (six of six) versus 33.3 percent (two of six); p = 0.014] CONCLUSION:: Postoperative patency of the lymphaticovenular anastomosis group was higher than that of the lymphaticovenous implantation group, although intraoperative patency rates of the lymphaticovenular anastomosis and lymphaticovenous implantation groups were comparable.


Increased frequency of visits improves the efficiency of surgical global health initiatives.
The Uganda Hearing Project is a non-profit program assisting with teaching of ear surgery in Uganda. The project started with cadaveric temporal bone courses in 2003 and 2005, including donation of operating microscopes and ear instruments. In 2006, three surgical groups started regular surgical teaching visits. A retrospective chart review of all cases of middle ear surgery performed in Uganda from 2003 to 2009. Surgeries by local surgeons without foreign presence were coded as 'local' and those performed with assistance of visiting surgeons were coded as 'visitors'. In 2005, two middle ear surgeries using the operating microscope were done in the Ugandan teaching hospitals by Ugandan Otolaryngologists alone. From the onset of surgical visits in 2006, a total of 193 middle ear surgeries were performed--115 tympanomastoidectomies, 77 tympanoplasties, and 1 cochlear implant. In 2006 (one surgical teaching visit), 6 middle ear surgeries were performed with visiting surgeon presence and 2 surgeries were performed by the local team alone. This increased in 2007 (2 visits) and again in 2008 (3 visits) to 34 cases with visiting surgeon presence and 48 local cases. The temporal bone courses and donation of operating microscopes to Ugandan hospitals have revolutionized middle ear surgery in Uganda. The surgical visits by the Uganda Hearing Project have led to a 24-fold increase in annual middle ear surgeries performed with the operating microscope by Ugandan Otolaryngologists. Increased frequency of surgical visits was correlated with an increase in local surgical output, hopefully resulting in improved care for Ugandans with ear disorders.


Construction of One- and Two-Dimensional Nanostructures by the Sequential Assembly of Quadruplex DNA Scaffolds.
A quadruplex-integrated assembly method is proposed for the organization and regulation of various nanoscale architectures. In this method, two types of one-dimensional DNA nanostructures formed by two well-designed GC-rich single strands assemble into two-dimensional (2D) DNA nanostructures based on the self-assembly of dimeric G-quadruplex and I-motif structures. Subsequently, a C-rich strand and two biotin-modified G-rich strands primordially form a notched double helix in LiCl solution (pH 8). However, a linear "DNA-protein" nanostructure linked by I-motif structures and biotin-streptavidin interaction can be formed when hydrogen ions and streptavidin are sequentially titrated. Furthermore, the linear "DNA-protein" nanostructure is assembled into 2D nanomaterials connected by K+-stabilized G-quadruplexes formed from terminal G-rich repeats of the two G-rich strands. Interestingly, the 2D nanohybrids form two-lined "DNA-protein" nanostructures if the terminal G-rich repeats in one of the biotin-modified G-rich strands are removed. Our results indicate that quadruplex DNAs are promising building blocks in the fabrication of nanomaterials and that the assembly of quadruplex DNAs has potential applications in the directional arrangement of macromolecules.


A dynamic alternative splicing program regulates gene expression during terminal erythropoiesis.
Alternative pre-messenger RNA splicing remodels the human transcriptome in a spatiotemporal manner during normal development and differentiation. Here we explored the landscape of transcript diversity in the erythroid lineage by RNA-seq analysis of five highly purified populations of morphologically distinct human erythroblasts, representing the last four cell divisions before enucleation. In this unique differentiation system, we found evidence of an extensive and dynamic alternative splicing program encompassing genes with many diverse functions. Alternative splicing was particularly enriched in genes controlling cell cycle, organelle organization, chromatin function and RNA processing. Many alternative exons exhibited differentiation-associated switches in splicing efficiency, mostly in late-stage polychromatophilic and orthochromatophilic erythroblasts, in concert with extensive cellular remodeling that precedes enucleation. A subset of alternative splicing switches introduces premature translation termination codons into selected transcripts in a differentiation stage-specific manner, supporting the hypothesis that alternative splicing-coupled nonsense-mediated decay contributes to regulation of erythroid-expressed genes as a novel part of the overall differentiation program. We conclude that a highly dynamic alternative splicing program in terminally differentiating erythroblasts plays a major role in regulating gene expression to ensure synthesis of appropriate proteome at each stage as the cells remodel in preparation for production of mature red cells.


Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions.
The differential diagnosis between recurrence of gliomas or brain metastases and this phenomenon is important in order to choose the best therapy and predict the prognosis but is still a big problem for physicians. The new emerging MRI, CT, and PET diagnostic modalities still lack sufficient accuracy. Radiolabeled choline and amino acids have been reported to show great tumor specificity. We studied the uptake kinetics of [18F]fluoromethyl-choline (FCH) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) by the T98G human glioblastoma cells from 20 to 120 min after irradiation either with photons at 2-10-20 Gy or with carbon ions at 2 Gy (at the National Centre for Oncological Hadrontherapy (CNAO), Pavia, Italy). We also evaluated the cell death and morphology changes induced by radiation treatment. Both FET and FCH are able to trace tumor behavior in terms of higher uptake for increased doses of radiation treatment, due to the upregulation of cells attempts to repair nonlethal damage. Our data suggest that both FCH and FET could be useful to analyze the metabolic pathways of glioblastoma cells before and after radiotherapy. Physicians will have to consider the different kinetics pathways of uptake concerning the two radiopharmaceuticals.


[Neuronal mechanisms underlying main clinical syndromes of post-traumatic stress disorder].
This review is designed to consider neurophysiological aspects of post-traumatic stress disorder (PTSD). Current concepts of enhanced activity of the sympathetic nervous system and the role of hypothalamo-pituitary-adrenal axis in the development of major clinical manifestations of PTSD are presented. Mechanisms of memory impairment, phobic reactions, hyperactivity, obsession, and sleep disturbances associated with PTSD are discussed. Special attention is given to the mechanism of pain syndrome under stress conditions and the role of impaired activity of stress-limiting (opioidergic and GABA-ergic) systems. Further studies of PTSD are needed with reference to individual differences of adaptive mechanisms depending on age, gender, and injury type. Of equal interest are co-morbid conditions and their relation to pathological changes in the brain. Studies of the involved mediator systems in different diseases, e.g. neurologic pathology concomitant with PTSD, are virtually absent. Better understanding of neurobiological mechanisms underlying these conditions may lead to the development of new therapeutic modalities.


Mouse fetal intestinal organoids: new model to study epithelial maturation from suckling to weaning.
During the suckling-to-weaning transition, the intestinal epithelium matures, allowing digestion of solid food. Transplantation experiments with rodent fetal epithelium into subcutaneous tissue of adult animals suggest that this transition is intrinsically programmed and occurs in the absence of dietary or hormonal signals. Here, we show that organoids derived from mouse primary fetal intestinal epithelial cells express markers of late fetal and neonatal development. In a stable culture medium, these fetal epithelium-derived organoids lose all markers of neonatal epithelium and start expressing hallmarks of adult epithelium in a time frame that mirrors epithelial maturation in vivoIn vitro postnatal development of the fetal-derived organoids accelerates by dexamethasone, a drug used to accelerate intestinal maturation in vivo Together, our data show that organoids derived from fetal epithelium undergo suckling-to-weaning transition, that the speed of maturation can be modulated, and that fetal organoids can be used to model the molecular mechanisms of postnatal epithelial maturation.


High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients.
Keratin 8 (KRT8), a type II basic intermediate filament (IF) protein, is essential for the development and metastasis of various cancers. In this study, by analyzing RNA-seq data from the Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), we have determined the expression profile of KRT8, and assessed its prognostic significance and the possible mechanism underlying the dysregulation. Our results showed that KRT8 mRNA expression was significantly up-regulated in both LUAD and LUSC tissues compared with normal lung tissues. The high KRT8 expression group for LUAD patients significantly reduced overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate analysis revealed that KRT8 expression was an independent prognostic indicator for poor OS and RFS in LUAD patients. However, KRT8 expression had no prognostic value in terms of OS and RFS for LUSC. By exploring DNA copy number alterations (CNAs) of the KRT8 gene in LUAD, we found that DNA low copy gain (+1 and +2) was associated with elevated KRT8 mRNA expression. From the above findings, we have deduced that KRT8 is aberrantly expressed in LUAD tissues and that its expression might independently predict poor OS and RFS for LUAD patients, but not for LUSC patients.


OxyContin and the McDonaldization of chronic pain therapy in the USA.
Principles and practices gleaned from successful business enterprises have been used to transform the practice of medicine for decades. McDonaldization is the process in which principles which govern fast-food businesses, are applied to the practice of medicine. When left unchecked, the application of these principles can have devastating consequences, as in the treatment of chronic, non-malignant pain with OxyContin. At a time when there was growing concern about the under treatment of pain, Purdue Pharma introduced OxyContin, providing an efficient, predictable way of treating chronic pain. The liberal prescription of this drug contributed, and continues to contribute, to the opioid epidemic we see today. So, in confronting this epidemic, we must first understand the process of McDonaldization that has brought us here and then provide safe and effective chronic pain therapies even if they are expensive, time-consuming to deliver, difficult to measure, and unpredictable in their outcomes-all things we've grown to detest in our McDonaldized healthcare system.


Screening primiparous women and newborns for fetal/neonatal alloimmune thrombocytopenia: a prospective comparison of effectiveness and costs. Immune Thrombocytopenia Working Group.
A prospective study was conducted in three maternity wards to compare the medical outcomes and the costs of two screening strategies for the detection of fetal/neonatal alloimmune thrombocytopenia (FMAIT). A total of 2066 primiparas and 6081 newborns were included. Fifty-two primiparous women with HPA-1b phenotype were found, and 45 were followed during pregnancy. Four women developed antibodies, and two fetuses exhibited FMAIT; therefore, the prevalence of anti-HPA-1a was 2 per 1000, and the prevalence of FMAIT 1 per 1000. Forty-eight thrombocytopenic newborns were found out of a total of 5632 blood samples. Five were HPA-1a children whose mothers were HPA-1b. The cost-effectiveness of screening all primiparous women was $45,000 and of screening all newborns is $18,000-per anti-HPA-1a alloimmunization diagnosed. Costs per fetal death or disability averted were $500,000 for the primiparous strategy and $225,000 for the newborn strategy. In conclusion, screening newborns for neonatal alloimmune thrombocytopenia is more cost-effective than screening primiparous women.


Analysis of Phylogenomic Tree Space Resolves Relationships Among Marsupial Families.
A fundamental challenge in resolving evolutionary relationships across the tree of life is to account for heterogeneity in the evolutionary signal across loci. Studies of marsupial mammals have demonstrated that this heterogeneity can be substantial, leaving considerable uncertainty in the evolutionary timescale and relationships within the group. Using simulations and a new phylogenomic data set comprising nucleotide sequences of 1550 loci from 18 of the 22 extant marsupial families, we demonstrate the power of a method for identifying clusters of loci that support different phylogenetic trees. We find two distinct clusters of loci, each providing an estimate of the species tree that matches previously proposed resolutions of the marsupial phylogeny. We also identify a well-supported placement for the enigmatic marsupial moles (Notoryctes) that contradicts previous molecular estimates but is consistent with morphological evidence. The pattern of gene-tree variation across tree-space is characterized by changes in information content, GC content, substitution-model adequacy, and signatures of purifying selection in the data. In a simulation study, we show that incomplete lineage sorting can explain the division of loci into the two tree-topology clusters, as found in our phylogenomic analysis of marsupials. We also demonstrate the potential benefits of minimizing uncertainty from phylogenetic conflict for molecular dating. Our analyses reveal that Australasian marsupials appeared in the early Paleocene, whereas the diversification of present-day families occurred primarily during the late Eocene and early Oligocene. Our methods provide an intuitive framework for improving the accuracy and precision of phylogenetic inference and molecular dating using genome-scale data.


[Tackle health inequality in prevention: state of the art through an assessment of 21 Regional preventive plan 2014-2018].
the Italian health policies awareness on health inequalities (HI) issues is increasing. The National Plan for health prevention and promotion (2014-2018) (PNP) introduced in 2014 a clear political commitment aimed at reducing HI. During 2015, each Italian regions (IRs) elaborated and approved by law its prevention plan (PRP), according to the PNP. To support this process, a factsheet describing educational inequalities (EIs) in the exposure to risk factors (RFs) was provided with training for many IRs. an evaluation of the 21 PRPs was performed to assess the level of adherence to the national direction and to investigate the impact of the availability of regional health inequalities data. a checklist for the evaluation of the PRP was developed and discussed with experts. Frequency of success was calculated for each dimension investigated in the 21 PRPs. An overall score assessing the regional level of adherence to the national recommendation was computed. 21 PRPs and 194 programmes were assessed. 13 PRPs considered the need to address HIs and 8 declared to have used quantitative information on HIs for priority setting; 8 PRPs monitored the magnitude of HIs, but only 6 decided to set specific actions tackling such disparities. Overall, 4 IRs failed to comply with the national recommendation to include equity in the PRP, while 14 faced the challenge with different level of engagement in equity. There is an association between the adherence to the equity recommendation and the availability of a regional factsheet. thanks to the national commitment and to the effort of dissemination of evidence on HIs tailored to each IR, it has been possible to bring many IRs to incorporate in some way the issue of equity in prevention in the majority of their PRP. However, evidence of high level of HI is neither sufficient nor necessary to encourage decision makers to raise equity in their agenda.


[Vertebral destruction with sever pain in the SAPHO syndrome].
A 57-year-old man had for the past 18 months complained of recurrent, recently worsening, belt-like backache radiating ventrally. On admission a skin rash consisting of blister and pustules was noted on the palms of both hands. He had pain on pressure over the right upper abdomen, an enlarged prostate and definite pain on percussing the vertebral column with restricted movement of the thoracic vertebral column, but no other physical signs. Radiology revealed clearly increased sclerosis of several thoracic vertebrae with osteolytic destruction and a paravertebral soft tissue tumor. Search for a primary tumor was unsuccessful. Bone scintigraphy demonstrated nuclide enrichment of the thoracic vertebrae and of the sternoclavicular joints without increase in the LeukoScan. These findings indicated the diagnosis of SAPHO syndrome (synovitis-acne-pustulosis-hyperostosis-osteomyelitis). Rapid subjective and objective improvement followed the administration of clindamycin and ibuprofen. In case of bone pain of uncertain aetiology, especially when associated with skin rash, the rare SAPHO syndrome should be considered in the differential diagnosis, avoiding lengthy diagnostic steps and allowing early treatment.


[Pharmaceuticals in the environment].
Drugs and their metabolites, once reached and spread over the soil and the aquatic environment, then exert their action on the living organisms belonging to such ecosystems. The present work provides a brief view on the main scientific experiences regarding the problem of the presence of drugs and/or their residues in the environment and of the related effects on the biokenosis and the human community.


Identification of a Common Conformational Epitope on the Glycoprotein E2 of Classical Swine Fever Virus and Border Disease Virus.
Classical swine fever virus (CSFV) shares high structural and antigenic homology with bovine viral diarrhea virus (BVDV) and border disease virus (BDV). Because all three viruses can infect swine and elicit cross-reactive antibodies, it is necessary to differentiate among them with regard to serological diagnosis of classical swine fever. To understand the mechanism of cross-reactivity, it is important to define common or specific epitopes of these viruses. For this purpose, epitope mapping of six monoclonal antibodies (mAbs) was performed using recombinant expressed antigenic domains of CSFV and BDV E2 proteins. One CSFV-specific conformational epitope and one CSFV and BDV common epitope within domain B/C of E2 were identified. Site-directed mutagenesis confirmed that residues G725 and V738/I738 of the CSFV-specific epitope and P709/L709 and E713 of the second epitope are important for mAbs binding. Infection of CSFV in porcine cells was significantly reduced after pre-incubation of the cells with the domain B/C of E2 or after pre-incubation of CSFV with the mAbs detecting domain B/C. 3D structural modeling suggested that both epitopes are exposed on the surface of E2. Based on this, the identified epitopes represent a potential target for virus neutralization and might be involved in the early steps of CSFV infection.


Immunologic and psychosocial status in chronic fatigue syndrome.
The aim of the study was to investigate the immunologic functions and psychosocial status in patients with chronic fatigue syndrome (CFS). Twenty-five patients with CFS diagnosed by the international CFS definition criteria and 20 age- and gender-matched healthy controls were recruited. Depression was assessed by Beck Depression Inventory (BDI) and health status was assessed by Nottingham Health Profile (NHP). Monoclonal antibodies (MAbs) were measured to identify the following NK cell subsets: CD3, CD4, CD8 and CD56 and cytokine measurements were performed for IL2r, IL6 and IL8 in both patients and control subjects. The BDI and NHP scores of CFS group were found to be significantly higher than in the control group. The absolute numbers of CD56 cell were also significantly decreased in the patients with CFS compared with the healthy controls. There were no other significant differences of NK cell activity (CD3, CD4 and CD8) and there were significant differences in IL6 and IL2r levels between patients and controls. There were significant correlations between serum IL-6 level and sleep, social isolation and physical ability NHP subscores, and betweenCD56 NK cell activity and emotional reaction NHP sub score in CFS patients. Significantly higher ratios of psychological and physical disturbances were found in patients with CFS. Decreased CD56 NK cell activity and increased IL2r levels seem to be important immunopathologic changes in CFS. IL-6 and CD 56 NK cell activity may play an important role in sleep, physical, social, and physicological manifestations of CFS (Tab. 3, Fig. 1, Ref. 36). Full Text in free PDF www.bmj.sk.


Biological nitration of arachidonic acid.
When a spontaneous autoxidation of arachidonic acid to prostaglandin-like products was first described almost 40 years ago, it was thought to be an artifact that interfered with the detection of enzymatically generated prostaglandins. It has now been generally accepted that the autoxidation of arachidonic acid occurs in vivo and leads to formation of isoprostanes and other products. Sensitive methods can detect the isoprostanes as useful biological markers, which help to estimate, non-invasively, the burden of free radicals formed in pathologies resulting from oxidative stress. After the discovery of NO, it has been hypothesized that NO and its active congeners (reactive nitrogen species, RNS), such as nitrogen dioxide radical (NO2), nitrous acid, peroxynitrite, can also participate in lipid peroxidation, either as initiators or modulators of processes initiated by the hydroxyl radical. In biological systems these RNS not only originate from the biosynthesis of NO but also from exogenous sources such as polluted air and dietary nitrite. While the ability of NO2 to induce lipid peroxidation has been long known, more recent studies have discovered novel processes that have been termed lipid nitration. Polyunsaturated fatty acids appear to be readily targeted by RNS. Among the products of arachidonic acid nitration by NO2, interesting lipids have been detected, such as nitroeicosatetraenoic acids, alpha,beta-nitrohydroxyeicosatrienoic acids, and trans-arachidonic acids. The products of fatty acid nitration have the potential to function as biomarkers and/or lipid mediators of mechanisms distinct from fatty acid peroxidation but offering insight into the contribution of specific RNS such as NO2 to the damage of biological membrane resulting from nitrooxidative stress.


A role for Cep70 in centriole amplification in multiciliated cells.
Centriole amplification in multiciliated cells occurs in a pseudo-cell cycle regulated process that typically utilizes a poorly characterized molecularly dense structure called the deuterosome. We identified the centrosomal protein Cep70 as a novel deuterosome-associated protein that forms a complex with other deuterosome proteins, CCDC78 and Deup1. Cep70 dynamically associates with deuterosomes during centriole amplification in the ciliated epithelia of Xenopus embryos. Cep70 is not found in nascent deuterosomes prior to amplification. However, it becomes localized at deuterosomes at the onset of centriole biogenesis and remains there after the completion of centriole amplification. Deuterosome localization requires a conserved C-terminal "Cep70" motif. Depletion of Cep70 using morpholino oligos or CRISPR/Cas9 editing in F0 embryos leads to a severe decrease in centriole formation in both endogenous MCCs, as well as ectopically induced MCCs. Consistent with a decrease in centrioles, endogenous MCCs have defects in the process of radial intercalation. We propose that Cep70 represents a novel regulator of centriole biogenesis in MCCs.


Congenital extensor tendon dislocation causing pseudotriggering of the little finger.
The main complaints in extensor tendon dislocations are pain, swelling, sense of discomfort, snapping and difficulty in writing and forceful flexion. However, congenital extensor tendon subluxations may present with triggering of the fingers due to tendon dislocations. Unnecessary A1 pulley release may be performed for pseudotriggerring with unsuccessful results. Here, we report an unusual case of congenital extensor tendon subluxation of multiple digits with triggering of the left little finger and aim to attract notice to pseudotriggering of the digits due to tendon dislocations. An extensor hood reconstruction performed by an extensor digitorum communis tendon slip which is passed beneath the deep intermetacarpal ligament is a successful choice of treatment for these patients.


Comparison of the Proportion and Healthcare Utilisation of Adult Patients with Uncontrolled Severe Asthma versus Non-Severe Asthma Seen in a Southeast Asian Hospital-Based Respiratory Specialist Clinic.
Understanding the burden of uncontrolled severe asthma is essential for disease-targeted healthcare planning. There is a scarcity of data regarding the proportion, healthcare utilisation and costs of patients with uncontrolled severe asthma in Asia. This study aimed to plug the knowledge gap in this area. Consecutive patients with asthma managed in our respiratory specialist clinic were evaluated prospectively. Healthcare utilisation comprising unscheduled asthma-related primary care visits, emergency department (ED) visits and hospital admissions were obtained from the national health records system. We defined uncontrolled severe asthma as poor symptom control (Asthma Control Test score <20); 2 or more asthma exacerbations requiring ≥3 days of systemic corticosteroids in the previous year; 1 or more serious asthma exacerbation requiring hospitalisation in the previous year; or airflow limitation with pre-bronchodilator forced expiratory volume in 1 second (FEV1) <80% predicted despite high dose inhaled corticosteroids and another controller medication. Of the 423 study participants, 49 (11.6%) had uncontrolled severe asthma. Compared to non-severe asthma, patients with uncontrolled severe asthma were older and more likely to be female and obese. They had a median of 2 (interquartile range: 0 to 3) exacerbations a year, with 51% having ≥2 exacerbations in the past 12 months. They were responsible for 43.9% of the hospital admissions experienced by the whole study cohort. Mean annual direct asthma costs per patient was S$2952 ± S$4225 in uncontrolled severe asthma vs S$841 ± S$815 in non-severe asthma. Approximately 12% of patients with asthma managed in a hospital-based respiratory specialist clinic in Singapore have uncontrolled severe asthma. They account for a disproportionate amount of healthcare utilisation and costs. Healthcare strategies targeting these patients are urgently needed.


A syndrome from a possible GABA deficiency. Clinical-therapeutic report on 15 cases.
A detailed presentation of 15 case-histories of subjects of both sexes, drawn from all decennies of life from the first to the eight, suggesting a syndrome originated from a possible GABA deficiency, is carefully made. Such syndrome is believed to be characterized by basic depressive state, loss of the habit of stretching oneself, sleep disorders, mostly with early morning awakening, constipation and nuchal headache. The above symptoms have been associated to a deficiency of GABA after noting the very speed recovery after administration of N-dipropylacetic acid, an inhibitor of GABA transaminase.


A study of the antioxidant effect of alpha lipoic acids on sperm quality.
Assisted reproductive techniques are useful in helping infertile couples achieve successful conception. Initial studies have shown that sperm cryopreservation, one step in assisted reproduction, causes a dramatic reduction in sperm quality. This has been attributed to, among other things, free radical activities. The aim of the present study was to minimize this oxidative attack by adding an antioxidant into the sperm microenvironment. Alpha lipoic acids were selected for this purpose for their efficient free radical scavenging properties and solubility in lipid and aqueous phases. For this investigation, semen from six Boer bucks was pooled. Seminal analysis of the baseline prior to incubation of samples with different concentrations of Alpha lipoic acids (0.00625, 0.0125, 0.025, 0.05, 0.1 mmol/ml) was performed, and post-seminal analysis was conducted after a one-hour incubation. The comet assay was used to observe the effect of Alpha lipoic acids on sperm DNA integrity. Statistical analysis using an unpaired t-test with a significance level of p<0.05 was then performed. Our results indicate that the sperm motility rate was improved after incubation with Alpha lipoic acids at a concentration of 0.02 mmol/ml. This concentration was also capable of reducing DNA damage. In conclusion, Alpha lipoic acids renders cryoprotection to sperm, thereby improving sperm quality.


Hexokinase and glucose-phosphoenolpyruvate phosphotransferase synthesis in Klebsiella aerogenes strains growing in continuous culture.
Considerable differences in steady-state hexokinase specific activity were found in 16 N.C.I.B. strains of Klebsiella aerogenes grown in identical conditions in glucose-limited chemostats. Strains of N.C.I.B. 8258 had no detectable activity, but its glucose-phosphoenolpyruvate phosphotransferase specific activity and that of the other strains were closely similar, and it is concluded that this phosphotransferase activity regulates the overall utilization of glucose, in which hexokinase plays no essential role. The hexokinase activity was subject to regulation by the availability of phosphorus, but this did not affect the glucose phosphotransferase activity. tlactose-grown organisms (including strain N.C.I.B. 8258) had no glucose phosphotransferase activity, but more than adequate hexokinase activity to phosphorylate the intracellularly liberated glucose.


Skin-to-skin care and breastfeeding in the perioperative suite.
Current trends are moving toward immediate skin-to-skin care after birth of a newborn. This is shown to be highly beneficial, both physiologically and emotionally, to the mother and the baby. Strategies and considerations for initiating skin-to-skin care in the perioperative suite immediately after cesarean birth, such as thermoregulation of the baby in the operative suite, equipment, baby and family positioning, and maternal monitoring, are presented. Initiating skin-to-skin care as soon as possible after birth is recommended.


Tuning the Structure and Photophysics of a Fluorous Phthalocyanine Platform.
Phthalocyanines are an important class of industrial dyes with potential commercial applications ranging from photovoltaics to biomedical imaging and therapeutics. We previously demonstrated the versatility of the commercially available zinc(II) hexadecafluorophthalocyanine (ZnF16Pc) as a platform for rapidly developing functional materials for these applications and more. Because this core-platform approach to dye development is increasingly common, it is important to understand the photophysical and structural consequences of the substitution chemistry involved. We present a fundamental study of a series of ZnF16Pc derivatives in which the aromatic fluorine atoms are progressively substituted with thioalkanes. Clear spectroscopic trends are observed as the substituents change from electron-withdrawing to electron-releasing groups. Additionally, there is evidence for significant structural distortion of the normally planar heterocycle, with important ramifications for the photophysics. These results are also correlated to DFT calculations, which show that the orbital energies and symmetries are both important factors for explaining the excited-state dynamics.


[Current problems in mass screening for breast cancer].
As the trend in the incidences of morbidity and mortality from breast cancer in Japan has been going up in recent years, mass screening for breast cancer is being undertaken on a nationwide scale. In Tokushima prefecture, 111,571 women (49,319 in actual number) were subjected to mass screening with physical examination from 1970-1984. In 116 including 26 cases of so-called "interval cancer", breast cancer was detected. Those with cancer detected by screening were in the earlier stage of the disease as compared to those diagnosed through regular medical care at our out-patient clinic during the same period. In the breast cancers detected by screening, the classifications of tumor size and lymph node involvement were not significantly different among the initial screening cases, subsequent screening cases and interval cases. The detection rate was 0.08% of total examinees, having 0.13% in the initial screening and 0.04% in the subsequent screening. The cancer was detectable mostly in patients aged over 60 and there were few cases in the younger generation. Repeat examinees accounted for 55.8% with an annual increase, but the proportion of initial examinees remained unchanged. Women in their 30s and 40s accounted for about 64.2% of all examinees. The results suggest that procedures such as inspection and palpation are useful for early detection of breast cancer among Japanese women. It is important to emphasize the following items for further improvement in our program, older women should be encouraged to actively participate in the screening, and percentage of initial examinees should be increased. Furthermore, the current objectives of mass screening for breast cancer are: to determine an appropriate screening survey method, to organize an adequate follow-up system for women with abnormal findings, and to educate the examinees in breast self-examination.


Antioxidant effect of vegetable oils containing conjugated linolenic acid isomers against induced tissue lipid peroxidation and inflammation in rat model.
The purpose of the present study was to examine the antioxidant activity of two typical oils obtained from two vegetables, bitter gourd seed and snake gourd seed, containing two different isomers of conjugated linolenic acid (CLnA) against oxidative stress induced by sodium arsenite in relation to tissue lipid peroxidation and inflammation. Male albino rats were taken as subject and divided into six groups: Group 1 was control and Group 2 was treated with sodium arsenite (Sa; 10mg/Kg BW); Groups 3-6 were orally treated with different doses of seed oils maintaining definite concentration of CLnA isomers (0.5% and 1.0% of total lipid for each CLnA isomer) along with sodium arsenite. There was significant increase in lipid peroxidation, pro-oxidant enzyme activity and decrease in antioxidant enzyme activity in brain due to Sa administration. Decrease in total protein content was also observed in plasma, liver and brain of Sa treated group. Significant decrease in phospholipid content and increase in total lipid content and cholesterol content were observed in arsenite treated group. There was significant increase in relative organ weight of liver due to Sa administration. Fatty acid profile of liver and brain lipid shows significant (P<0.05) reduction in most of the polyunsaturated fatty acids and increase in arachidonic acid (20:4n-6) (75.23%) due to inflammation after arsenite treatment. Administration of experimental oils made almost complete restoration of those altered parameters. Overall, these two oils were effective in protecting tissue lipid profiles which were altered due to oxidative stress.


Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease.
It is not clear whether there is benefit in repeating the dose of prenatal corticosteroids for women who remain at risk of preterm birth after an initial course. To assess the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 4), MEDLINE (1965 to November 2006), EMBASE (1988 to November 2006) and Current Contents (1997 to November 2006). Randomised controlled trials of women who have already received a single course of corticosteroids seven or more days previously and are still considered to be at risk of preterm birth; outcomes compared for women randomised to receive a repeat dose(s) of prenatal corticosteroids, with women given no further prenatal corticosteroids. We assessed trial quality and extracted the data independently. Five trials, involving over 2000 women between 23 and 33 weeks' gestation, are included. Treatment with repeat dose(s) of corticosteroid was associated with a reduction in occurrence (relative risk (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.93, four trials, 2155 infants) and severity of any neonatal lung disease (RR 0.60, 95% CI 0.48 to 0.75, three trials, 2139 infants) and serious infant morbidity (RR 0.79, 95% CI 0.67 to 0.93, four trials, 2157 infants).Mean birthweight was not significantly different between treatment groups (weighted mean difference (WMD) -62.07 g, 95% CI -129.10 to 4.96, four trials, 2273 infants), although in one trial, treatment with repeat dose(s) of corticosteroid was associated with a reduction in birthweight Z score (WMD) -0.13, 95% CI -26 to 0.00, 1 trial, 1144 infants), and in two trials, with an increased risk of being small for gestational age at birth (RR 1.63, 95% CI 1.12 to 2.37, two trials, 602 infants). No statistically significant differences were seen for any of the other primary outcomes that included other measures of respiratory morbidity, fetal and neonatal mortality, periventricular haemorrhage, periventricular leukomalacia and maternal infectious morbidity. Treatment with repeat dose(s) of corticosteroid was associated with a significantly increased risk of caesarean section (RR 1.11, 95% CI 1.01 to 1.22, four trials, 1523 women). Repeat dose(s) of prenatal corticosteroids reduce the occurrence and severity of neonatal lung disease and the risk of serious health problems in the first few weeks of life. These short-term benefits for babies support the use of repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth. However, these benefits are associated with a reduction in some measures of weight, and head circumference at birth, and there is still insufficient evidence on the longer-term benefits and risks.


Psychometric characteristics of the Muslim Religiosity Scale in Iranian patients with cancer.
Cancer is a leading cause of death worldwide. Religiosity is a factor that may help cancer patients to cope with their disease. The aim of the current study was to validate a Persian translation of the Muslim Religiosity Scale (MRS) in a population of Iranian patients with cancer. Two thousand patients were invited to participate in this multisite study, of whom 1,879 participated. Patients completed a demographic questionnaire, the MRS, and several scales, including the Patient Health Questionnaire-9, the Hospital Anxiety and Depression Scale, the Perceived Social Support Scale, and the SF-12 quality of life measure. Backward-forward translation was employed to develop a Persian-language version of the MRS. Cronbach's alpha and two-week test-retest reliability were also assessed. Convergent and discriminative validity as well as the factor structure of the scale were also examined. The internal reliability (α) of the religious practices and beliefs subscales was 0.88 and 0.92, respectively. The intraclass correlation coefficient (ICC) was 0.92 (range = 0.75-1.0). The scale demonstrated solid convergent and discriminative validity. Factor analysis indicated two main factors, as predicted, with an appropriate goodness of fit (χ2 = 76.23, RMSEA = 0.065). Such factors as marital status, quality of life, social support, and self-efficacy were positively associated with MRS total score, while anxiety, depression, and suicide ideation had negative associations. The MRS is a useful tool for assessing religiosity in Iranian patients with cancer and is associated with a number of important health outcomes.


Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III). All three groups received identical doses of prednisone (1 mg/kg every other day) and one double-strength trimethoprim-sulfamethoxazole (TMP-SMX) tablet twice daily. Between January 1980 and December 1983, 179 previously untreated patients were enrolled and 164 were evaluable. Patients randomized to group I (n = 63) and group II (n = 63) were well matched for prognostic factors; those placed into group III (n = 38) had more frequent acute GVHD and progressive onset of chronic GVHD. Median duration of therapy was 2 years. Complications included diabetes (5%), aseptic necrosis (5%) and infection. For groups I, II, and III, the respective incidence of infection was disseminated varicella, 11%, 24%, 34%; bacteremia, 6%, 11%, 34%; and interstitial pneumonia, 5%, 14%, 18%. Recurrent malignancy was the most frequent cause of death and did not differ significantly across the groups. Nonrelapse mortality, however, did differ: 21% in group I, 40% in group II, and 58% in group III (I v II, P = .003; I v III, P = .001). Forty patients in group I, 30 in group II, and 10 in group III survive with a minimum follow-up of 3.8 years. Karnofsky performance scores for 68 survivors are 90% to 100%, scores for seven survivors are 70% to 89% and scores for five survivors are less than 70%. Actuarial survival at 5 years after transplant is 61% in group I, 47% in group II, and 26% in group III (I v II, P = .03; I v III, P = .0001). Treatment with prednisone alone results in fewer infections and better survival than prednisone and azathioprine in standard-risk chronic GVHD. Treatment with prednisone alone is less effective in high-risk patients with thrombocytopenia, and other strategies are required.


Incidence of and risk factors for severe cardiovascular collapse after endotracheal intubation in the ICU: a multicenter observational study.
Severe cardiovascular collapse (CVC) is a life-threatening complication after emergency endotracheal intubation (ETI) in the ICU. Many factors may interact with hemodynamic conditions during ETI, but no study to date has focused on factors associated with severe CVC occurrence. This study assessed the incidence of severe CVC after ETI in the ICU and analyzed the factors predictive of severe CVC. This was a secondary analysis of a prospective multicenter study of 1,400 consecutive intubations at 42 ICUs. The incidence of severe CVC was assessed in patients who were hemodynamically stable (mean arterial blood pressure >65 mmHg without vasoactive drugs) before intubation, and the factors predictive of severe CVC were determined by multivariate analysis based on patient and procedure characteristics. Severe CVC occurred following 264 of 885 (29.8 %) intubation procedures. A two-step multivariate analysis showed that independent risk factors for CVC included simple acute physiologic score II regardless of age (odds ratio (OR) 1.02, p < 0.001), age 60-75 years (OR 1.96, p < 0.002 versus <60 years) and >75 years (OR 2.81, p < 0.001 versus <60 years), acute respiratory failure as a reason for intubation (OR 1.51, p = 0.04), first intubation in the ICU (OR 1.61, p = 0.02), noninvasive ventilation as a preoxygenation method (OR 1.54, p = 0.03) and inspired oxygen concentration >70 % after intubation (OR 1.91, p = 0.001). Comatose patients who required ETI were less likely to develop CVC during intubation (OR 0.48, p = 0.004). CVC is a frequent complication, especially in old and severely ill patients intubated for acute respiratory failure in the ICU. Specific bundles to prevent CVC may reduce morbidity and mortality related to intubation of these high-risk, critically ill patients. clinicaltrials.gov NCT01532063 ; registered 8 February 2012.


Nintendo Wii video-gaming ability predicts laparoscopic skill.
Studies using conventional consoles have suggested a possible link between video-gaming and laparoscopic skill. The authors hypothesized that the Nintendo Wii, with its motion-sensing interface, would provide a better model for laparoscopic tasks. This study investigated the relationship between Nintendo Wii skill, prior gaming experience, and laparoscopic skill. In this study, 20 participants who had minimal experience with either laparoscopic surgery or Nintendo Wii performed three tasks on a Webcam-based laparoscopic simulator and were assessed on three games on the Wii. The participants completed a questionnaire assessing prior gaming experience. The score for each of the three Wii games correlated positively with the laparoscopic score (r = 0.78, 0.63, 0.77; P < 0.001), as did the combined Wii score (r = 0.82; P < 0.001). The participants in the top tertile of Wii performance scored 60.3% higher on the laparoscopic tasks than those in the bottom tertile (P < 0.01). Partial correlation analysis with control for the effect of prior gaming experience showed a significant positive correlation between the Wii score and the laparoscopic score (r = 0.713; P < 0.001). Prior gaming experience also correlated positively with the laparoscopic score (r = 0.578; P < 0.01), but no significant difference in the laparoscopic score was observed when the participants in the top tertile of experience were compared with those in the bottom tertile (P = 0.26). The study findings suggest a skill overlap between the Nintendo Wii and basic laparoscopic tasks. Surgical candidates with advanced Nintendo Wii ability may possess higher baseline laparoscopic ability.


New Evidence of Skin Color Bias and Health Outcomes Using Sibling Difference Models: A Research Note.
In this research note, we use data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to determine whether darker skin tone predicts hypertension among siblings using a family fixed-effects analytic strategy. We find that even after we account for common family background and home environment, body mass index, age, sex, and outdoor activity, darker skin color significantly predicts hypertension incidence among siblings. In a supplementary analysis using newly released genetic data from Add Health, we find no evidence that our results are biased by genetic pleiotropy, whereby differences in alleles among siblings relate to coloration and directly to cardiovascular health simultaneously. These results add to the extant evidence on color biases that are distinct from those based on race alone and that will likely only heighten in importance in an increasingly multiracial environment as categorization becomes more complex.


JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit Ito Potassium Channels in Cardiomyocytes.
Kv4 potassium channels are responsible for transient outward K+ currents in the cardiac action potential (AP). Previous experiments by our group demonstrated that Jingzhaotoxin-V (JZTX-V) selectively inhibits A-type potassium channels. However, the specific effects of JZTX-V on the transient outward (Ito) current of cardiomyocytes and underlying mechanism of action remain unclear. In the current study, 100 nM JZTX-V effectively inhibited the Ito current and extended the action potential duration (APD) of neonatal rat ventricular myocytes (NRVM). We further analyzed the effects of JZTX-V on Kv4.2, a cloned channel believed to underlie the Ito current in rat cardiomyocytes. JZTX-V inhibited the Kv4.2 current with a half-maximal inhibitory concentration (IC50) of 13 ± 1.7 nM. To establish the molecular mechanism underlying the inhibitory action of JZTX-V on Kv4.2, we performed alanine scanning mutagenesis of Kv4.2 and JZTX-V and assessed the effects of the mutations on binding activities of the proteins. Interestingly, the Kv4.2 mutations V285A, F289A, and V290A reduced the affinity for JZTX-V while I275A and L277A increased the affinity for JZTX-V. Moreover, mutation of positively charged residues (R20 and K22) of JZTX-V and the hydrophobic patch (formed by W5, M6, and W7) led to a significant reduction in toxin sensitivity, indicating that the hydrophobic patch and electrostatic interactions played key roles in the binding of JZTX-V with Kv4.2. Data from our study have shed light on the specific roles and molecular mechanisms of JZTX-V in the regulation of Ito potassium channels and supported its utility as a potential novel antiarrhythmic drug.


Characterization of saccharide-CRM197 conjugate vaccines.
A seven-valent pneumococcal conjugate and a Group C Meningococcal conjugate are at the late stage of development. Clinical studies have demonstrated the efficacy and safety of these vaccines and licensure of these vaccines will be approved in the near future. Several new techniques have been proposed for characterizing polysaccharide-protein conjugates and their production intermediates. We are evaluating some of these new techniques, particularly NMR and MALLS, to determine whether or not they provide useful information for conjugate production. In the production of polysaccharide protein conjugates, the degree of saccharide activation, location of activation site, and the molecular weight of activated saccharides may typically be determined. In our evaluation, techniques such as NMR and MALLS may have a limited applicability for testing polysaccharides and activated saccharides.


Idarubicin in the intravesical treatment of superficial transitional-cell carcinoma of the bladder (ta-t1) - a phase I-ii study.
Local recurrences of superficial transitional cell carcinoma of the bladder (TCCB) can be significantly reduced by intravesical treatment following transurethral resection (TUR) but they are not fully abolished. There is a need to gain experience with new agents. Anthracyclines, such as doxorubicin and epirubicin, have been clearly demonstrated to be active against superficial TCCB by intravesical route. Idarubicin is an anthracycline, much more lipophilic than doxorubicin, inhibiting tumour cell growth at lower concentrations. The aim of this study was to evaluate the tolerability and the ablative efficacy on a marker lesion of weekly intravesical instillations of idarubicin given at different doses and concentrations. Seventeen patients, affected by superficial TCCB, Ta-T1 G1-G2, after TUR of all tumours except one, that was used as a 'marker lesion', were treated intravesically with idarubicin weekly for two months. The drug, in the first 4 patients, was administered at the dose of 15 mg diluted in 30 mi of normal saline solution and maintained in the bladder for one hour. Because of severe chemical cystitis, the dose was reduced to 10 mg in 40 mi in the following 13 patients. The study was closed because of the severe local toxicity. In eight (47%) patients the treatment was interrupted for local toxicity between the first and sixth week and in 5 more patients pharmacological therapy was required because of severe chemical cystitis. No systemic toxicity was evident. Three patients achieved a complete response. Our experience shows that idarubicin is not indicated in the intravesical therapy of superficial TCCB because of severe chemical cystitis limiting the administration of doses able to explicate a relevant antitumoral action.


Chronic nicotine exposure attenuates proangiogenic activity on human umbilical vein endothelial cells.
The pathogenic mechanism of nicotine, a major product of smoking, on vascular endothelial cells is not well defined yet. The purpose of this study was to determine whether chronic exposure to nicotine alters angiogenic activity in human umbilical vein endothelial cells and to identify a potential role for endothelial nitric oxide synthase (eNOS) expression. Our study demonstrated that acute nicotine treatment enhanced nitric oxide release, eNOS activation, and proangiogenic activity. However, chronic nicotine exposure impaired proangiogenic function (decreased cell migration and tubular structure formation) in human umbilical vein endothelial cells compared with acute exposure, but sustained the antiapoptotic effect. These findings seem to be related to eNOS gene expression and nitric oxide production, which may be involved in the pathophysiology of chronic nicotine addicts.


Disposition of hexobarbitone and antipyrine in DOCA-hypertensive rats.
The disposition of antipyrine and hexobarbitone, and their effects on drug metabolizing hepatic enzymes have been investigated in DOCA-hypertensive rats. Antipyrine pharmacokinetic parameters were the same in hypertensive and control animals. Hexobarbitone sleeping time was longer in hypertensive rats compared with controls, while the activity of hepatic hexobarbitone hydroxylase was the same in both groups. Hepatic aminopyrine-N-demethylase activity was elevated in hypertensive rats while aniline hydroxylase and aryl hydrocarbon hydroxylase were lower. Glucuronyl transferase was the same in both groups. The sensitivity of the central nervous system of hypertensive rats to hexobarbitone was not altered, as determined by hexobarbitone concentration in blood and in brain. The total hepatic blood flow (arterial and portal) was significantly increased. Thus it is suggested that the difference in the disposition of the two drugs is probably not due to drug metabolizing enzyme activity. It is likely that the increase in total hepatic blood flow and rapid saturation of hepatic hexobarbitone metabolizing enzymes have significant roles in the slower metabolism and increased activity of hexobarbitone in hypertensive rats as compared with control rats.


Genital herpes: an increasing problem?
Over the past 10 years there has been a pronounced increase in the number of cases of genital herpes seen in sexually transmitted disease (STD) clinics in the United Kingdom. The reporting system, however, does not differentiate between primary and recurrent infections, and consequently any increase in the number of patients reattending clinics with recurrent genital herpes would falsely inflate the statistics. A study of cases of herpes seen in the department of genitourinary medicine of this hospital in the two years 1972 and 1982 is presented. It showed that the proportion of patients attending with recurrent herpes had increased from 18% in 1972 to 31% in 1982. As a result of this, the 68% increase between 1972 and 1982 in the total number of cases of herpes seen in the clinic overestimates the real increase in the size of the problem, which is closer to 40%, based upon cases of primary herpes only. Modifications to the national recording system are necessary to overcome the problems highlighted by this study. These modifications could include classifying each case of genital herpes as primary, recurrent, or recurrent but not previously recorded, which would provide a more accurate picture of the size of the problem of genital herpes in the population.


[Progress in and outcomes of neonatal surgery over the past 50 years].
The Japanese Society of Pediatric Surgeons has performed a nationwide survey of neonatal surgery every 5 years during the 50 years since its foundation. The number of neonatal surgical cases has increased 5-fold during those 50 years, while the mortality rate has decreased from 60% to 15% for the main life-threatening diseases (such as esophageal atresia, diaphragmatic hernia, omphalocele, and gastroschisis). Currently, most neonatal patients who undergo surgery for severe cardiac or chromosomal anomalies survive. Therefore, pediatric surgeons are aware of the need for cosmetic considerations. Endoscopic surgical procedures and incisions using natural skin creases have been developed to achieve good cosmetic results and improve patients' quality of life. On the other hand, severe life-threatening neonatal surgical cases are still seen, such as patients with diaphragmatic hernia accompanied by severe pulmonary hypoplasia, huge sacrococcygeal teratomas, and neonatal intestinal perforation. Fetal intervention or early delivery should be considered to improve survival. Appropriate initial treatment strategies for intestinal perforation in very low birth-weight infants are needed.


Breath Biomarkers to Measure Uptake of Volatile Organic Compounds by Bicyclists.
Breath biomarkers were used to study uptake of traffic-related volatile organic compounds (VOCs) from urban bicycling. Breath analysis was selected because it is one of the least invasive methods to assess urban traveler exposure. Research hurdles that were overcome included considering that factors other than on-road exposure can influence concentrations in the body, and absorbed doses during a trip can be small compared to baseline body burdens. Pre-trip, on-road, and post-trip breath concentrations and ambient air concentrations were determined for 26 VOCs for bicyclists traveling on different path types. Statistical analyses of the concentration data identified eight monoaromatic hydrocarbons potentially useful as breath biomarkers to compare differences in body levels brought about by urban travel choices. Breath concentrations of the biomarker compounds were significantly higher than background levels after riding on high-traffic arterial streets and on a path through a high-exposure industrial area, but not after riding on low-traffic local streets or on other off-street paths. Modeled effects of high-traffic streets on ambient concentrations were 100-200% larger than those of low-traffic streets; modeled effects of high-traffic streets on breath concentrations were 40-100% larger than those of low-traffic streets. Similar percentage increases in breath concentrations are expected for bicyclists in other cities.


Non-peptide arginine-vasopressin antagonists: the vaptans.
Arginine-vasopressin is a hormone that plays an important part in circulatory and water homoeostasis. The three arginine-vasopressin-receptor subtypes--V1a, V1b, and V2--all belong to the large rhodopsin-like G-protein-coupled receptor family. The vaptans are orally and intravenously active non-peptide vasopressin receptor antagonists that are in development. Relcovaptan is a selective V1a-receptor antagonist, which has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhoea, and tocolysis. SSR-149415 is a selective V1b-receptor antagonist, which could have beneficial effects in the treatment of psychiatric disorders. V2-receptor antagonists--mozavaptan, lixivaptan, satavaptan, and tolvaptan--induce a highly hypotonic diuresis without substantially affecting the excretion of electrolytes (by contrast with the effects of diuretics). These drugs are all effective in the treatment of euvolaemic and hypervolaemic hyponatraemia. Conivaptan is a V1a/V2 non-selective vasopressin-receptor antagonist that has been approved by the US Food and Drug Administration as an intravenous infusion for the inhospital treatment of euvolaemic or hypervolaemic hyponatraemia.


[Symptomatic low-energy shockwave therapy in heel pain and radiologically detected plantar heel spur].
The long-term analgetic effect of low-energetic shock-wave therapy in heel spur for two different numbers of applicated impulses is investigated. 50 patients with recalcitrant heel pain and a plantar calcaneal spur on the X-ray received in a controlled, prospective and randomized study low-energetic extracorporal shock-wave-therapy. The first group received 3 x 500 impulses and the second group 3 x 100 impulses of 0.08 mJ/mm2 with an experimental device. The follow-up was 1 1/2, 3 and by telephone after 12 months. There was clear improvement and relief of pain in both groups on manual pressure and while walking and an increase of the pain-free walking ability from 10 minutes before the treatment to 2 and 3 hours respectively after 12 months. We saw a significantly better results after the treatment with 3 x 500 impulses. The extracorporal shock-wave therapy is an effective treatment in refractory heel pain. An amount of at least 3 x 500 impulses in the low energetic treatment is useful.


Quantifying Platelet Margination in Diabetic Blood Flow.
Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes, and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls, whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a nonmonotonic variation with the highest near-wall concentration corresponding to platelets with a moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tends to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.


African trypanosomes contain 5-methylcytosine in nuclear DNA.
It is currently unclear if there are modified DNA bases in Trypanosoma brucei other than J-base. We identify herein a cytosine-5 DNA methyltransferase gene and report the presence and location of 5-methylcytosine in genomic DNA. Our data demonstrate that African trypanosomes contain a functional cytosine DNA methylation pathway.


Hypovitaminosis D and Aging: Is There a Role in Muscle and Brain Health?
The older-adult population is constantly increasing, hence aging and mechanisms leading to aging are a topic raising increasing interest. Hypovitaminosis D is common amongst old patients and has been proposed as causative of several chronic diseases. Here we review the role of hypovitaminosis D and vitamin D supplementation in sarcopenia and dementia, from bench to bedside.


A job-exposure matrix for use in population based studies in England and Wales.
The job-exposure matrix described has been developed for use in population based studies of occupational morbidity and mortality in England and Wales. The job axis of the matrix is based on the Registrar General's 1966 classification of occupations and 1968 classification of industries, and comprises 669 job categories. The exposure axis is made up of 49 chemical, physical, and biological agents, most of which are known or suspected causes of occupational disease. In the body of the matrix associations between jobs and exposures are graded to four levels. The matrix has been applied to data from a case-control study of lung cancer in which occupational histories were elicited by means of a postal questionnaire. Estimates of exposure to five known or suspected carcinogens (asbestos, chromates, cutting oils, formaldehyde, and inhaled polycyclic aromatic hydrocarbons were compared with those obtained by detailed review of individual occupational histories. When the matrix was used exposures were attributed to jobs more frequently than on the basis of individual histories. Lung cancer was significantly more common among subjects classed by the matrix as having potential exposure to chromates, but neither method of assigning exposures produced statistically significant associations with asbestos or polycyclic aromatic hydrocarbons. Possible explanations for the failure to show a clear effect of these known carcinogens are discussed. The greater accuracy of exposures inferred directly from individual histories was reflected in steeper dose response curves for asbestos, chromates, and polycyclic aromatic hydrocarbons. The improvement over results obtained with the matrix, however, was not great. For occupational data of the type examined in this study, direct exposure estimates offer little advantage over those provided at lower cost by a matrix.


[Inhibition of kinase activity of the adrenal pyruvate dehydrogenase complex by the mitochondrial component].
A component inhibiting the phosphorylation-linked inactivation of the adrenal pyruvate dehydrogenase complex in the presence of ATP was revealed during purification of the complex from bovine adrenal mitochondria. The degree of the kinase activity inhibition is greater at lower concentrations of ATP. It was assumed that the mitochondrial component screens the kinase active site or the phosphorylation sites of pyruvate dehydrogenase, thus limiting the ATP access to them. Proteins and lipids are incorporated into the component at a ratio 2:1, which is suggestive of its lipoprotein nature. The effect of the mitochondrial component on the kinase activity of the pyruvate dehydrogenase complex is somewhat specific and is unaffected by bovine serum albumin or blood serum lipoproteins.


Exhaustive prediction of disease susceptibility to coding base changes in the human genome.
Single Nucleotide Polymorphisms (SNPs) are the most abundant form of genomic variation and can cause phenotypic differences between individuals, including diseases. Bases are subject to various levels of selection pressure, reflected in their inter-species conservation. We propose a method that is not dependant on transcription information to score each coding base in the human genome reflecting the disease probability associated with its mutation. Twelve factors likely to be associated with disease alleles were chosen as the input for a support vector machine prediction algorithm. The analysis yielded 83% sensitivity and 84% specificity in segregating disease like alleles as found in the Human Gene Mutation Database from non-disease like alleles as found in the Database of Single Nucleotide Polymorphisms. This algorithm was subsequently applied to each base within all known human genes, exhaustively confirming that interspecies conservation is the strongest factor for disease association. For each gene, the length normalized average disease potential score was calculated. Out of the 30 genes with the highest scores, 21 are directly associated with a disease. In contrast, out of the 30 genes with the lowest scores, only one is associated with a disease as found in published literature. The results strongly suggest that the highest scoring genes are enriched for those that might contribute to disease, if mutated. This method provides valuable information to researchers to identify sensitive positions in genes that have a high disease probability, enabling them to optimize experimental designs and interpret data emerging from genetic and epidemiological studies.


Parents' experience and meaning construction of the loss of a child in a national terror attack.
This paper describes a qualitative study aimed at exploring the meanings that are given by parents to the loss of their children in terror attacks in Israel and examining how specific aspects of these meanings help or hinder them in coping with the loss. This paper focuses the collective context of loss, a theme that emerged from in-depth interviews with 16 bereaved parents who lost their children in different terror attacks. The collective context of loss includes three subthemes: (a) the loss in the context of Jewish and Israeli history; (b) assigning responsibility for the loss; and (c) using the collective meaning in the process of coping. Overall, the findings highlight the role of the sociocultural context in the bereavement process. The discussion raises possible explanations for the significance of this role, focusing on the reciprocal processes between the bereaved parents and society, which are functional and effective for both.


Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients.
The expression of microRNAs (miRNAs) is a promising prognostic and diagnostic tool in hepatocellular carcinoma (HCC). Here we performed small RNA sequencing (sRNA-seq) of tissue, serum and serum exosomes to investigate changes in miRNA expression between the different sample types and correlated the expression with clinical parameters. We also performed gene expression arrays on tumor and normal tissue. Paired tissue, serum and serum exosomes sequencing revealed consistent positive correlation of miR-21 between serum exosomes and tumor tissue, indicating that miR-21 could be exported from tissue to circulation via exosomes. We found that let-7 miRNAs are generally upregulated in serum exosomes compared to whole serum, indicating that these miRNAs could be preferentially loaded into exosomes. Comparing serum from HCC patients with serum from healthy individuals revealed a global increase of miRNAs in serum from HCC patients, including an almost 4-fold increase of several miRNAs, including the liver-specific miR-122. When correlating miRNA expression with clinical parameters we detected significant association between hepatitis B virus (HBV) infection and miR-122 in serum as well as several serum and tissue-miRNAs that correlated with surgery type. We found that miR-141 and miR-146 correlated with cirrhosis in tumor tissue and normal tissue, respectively. Finally, high expression of miR-21 in tumors were associated with poor survival. Focusing on gene expression we found several significant messenger RNAs (mRNAs) between tumor and normal tissue and a Gene Ontology (GO) analysis revealed that these changes were mainly related to cell cycle and metabolism. Further, we detected mRNAs that correlated with cirrhosis and HBV infection in tissue. Finally, GO analysis of predicted targets for miRNAs down-regulated in tumor found that these were enriched for functions related to collagen synthesis. Our combined data point to altered miRNA and mRNA expression contributing to both generally impaired lipid metabolism and increased cell proliferation and a miRNA-driven increase in collagen synthesis in HCC. Our results further indicate a correlation in miRNA expression between exosomes, serum, and tissue samples suggesting export from tumors via exosomes. This correlation could provide a basis for a more tumor-specific miRNA profile in serum.


Gonadotrophic regulation of prolactin mediated progesterone secretion in vitro.
The effects of preincubating rat granulosa cells with FSH, LH, and Prl on subsequent Prl mediated progesterone secretion were investigated. Granulosa cells were isolated from ovarian follicles 50 h after injection of 5 IU PMSG and were then plated on poly-L-lysine coated coverslips in serum supplemented medium. Cells were preincubated for 24 h in the absence of hormones (control) or with the addition of either 0.25, 2.5, 25 ng/ml rat FSH or rat LH, or 1 microgram/ml rat Prl. Following the preincubation period, cells were maintained for an additional 6 or 8 days in the presence or absence of 1 microgram/ml Prl. When cells were preincubated with FSH or LH, only the two higher concentrations (2.5 and 25 ng/ml) stimulated significantly more progesterone secretion than control cultures during the 24 h preincubation period. For each series of preincubations, cells cultured for 6 or 8 days in the presence of Prl secreted significantly more progesterone at each day of culture than cells cultured without Prl. Cells preincubated and cultured with Prl secreted only 3-7-fold more progesterone than cells preincubated in control medium and then cultured with Prl. Preincubation with FSH or LH promoted a 20-45-fold increase in Prl mediated progesterone secretion compared to control preincubation cultures that also subsequently were cultured with Prl. The magnitude of Prl mediated progesterone secretion observed through 6 days of culturing was dose dependent on the preincubation concentration of FSH or LH.(ABSTRACT TRUNCATED AT 250 WORDS)


Detection of urease in the cell wall and membranes from leaf tissues of bromeliad species.
Urea is an important nitrogen source for some bromeliad species, and in nature it is derived from the excretion of amphibians, which visit or live inside the tank water. Its assimilation is dependent on the hydrolysis by urease (EC: 22.214.171.124), and although this enzyme has been extensively studied to date, little information is available about its cellular location. In higher plants, this enzyme is considered to be present in the cytoplasm. However, there is evidence that urease is secreted by the bromeliad Vriesea gigantea, implying that this enzyme is at least temporarily located in the plasmatic membrane and cell wall. In this article, urease activity was measured in different cell fractions using leaf tissues of two bromeliad species: the tank bromeliad V. gigantea and the terrestrial bromeliad Ananas comosus (L.) Merr. In both species, urease was present in the cell wall and membrane fractions, besides the cytoplasm. Moreover, a considerable difference was observed between the species: while V. gigantea had 40% of the urease activity detected in the membranes and cell wall fractions, less than 20% were found in the same fractions in A. comosus. The high proportion of urease found in cell wall and membranes in V. gigantea was also investigated by cytochemical detection and immunoreaction assay. Both approaches confirmed the enzymatic assay. We suggest this physiological characteristic allows tank bromeliads to survive in a nitrogen-limited environment, utilizing urea rapidly and efficiently and competing successfully for this nitrogen source against microorganisms that live in the tank water.


A randomized controlled trial comparing the effects of counseling and alarm device on HAART adherence and virologic outcomes.
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting. A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49-1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21-0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65-1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53-1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution. Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.


GRADE system: new paradigm.
An exposition of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to recommendations. In this review, we outline the process whereby the strength of evidence from the literature undergoes a systematic reappraisal. The GRADE system allows four grades of evidence (high quality, moderate, low, and very low) and strength of recommendation is qualified as strong, weak, or conditional to an intervention (pro or con) and defined as the level of confidence that desirable effects predominate over untoward ones with a certain intervention. We provide research and clinical reviews in various settings in which this approach has been used. Evidence-based medicine requires integrating the best available 'benchmark' literature with patient preferences and values (bedside) and is an evaluation process involving both patient and clinician, with a systematic assessment of the rated evidence from state-of-the-art medical literature. The GRADE methodology was developed as an application of evidence-based medicine to the field of recommendations and their formulation. The GRADE working group brings together clinical researchers and methodologists who developed a rating system to assess the quality of evidence for the purpose of making clinical practice recommendations.


Using semantic feature analysis to improve contextual discourse in adults with aphasia.
Semantic feature analysis (SFA) was used to determine whether training contextually related words would improve the discourse of individuals with nonfluent aphasia in preselected contexts. A modified multiple-probes-across-behaviors design was used to train target words using SFA in 3 adults with nonfluent aphasia. Pretreatment, posttreatment, and follow-up sessions obtained language samples for the preselected contexts. Contexts included 4 story retellings and 4 procedure explanations. All participants improved naming ability for treated words. No generalization to untrained items was found. Within discourse samples, participants increased number of target words produced from pretreatment to posttreatment sessions but did not increase lexical diversity across samples. Participants maintained performance on standardized measures from the beginning to the end of the study. Results support and extend previous research by indicating that SFA improves confrontational naming ability and may benefit word retrieval in discourse production of closed-set contexts.


Attention bias to threat faces in severe mood dysregulation.
We used a dot-probe paradigm to examine attention bias toward threat (i.e., angry) and happy face stimuli in severe mood dysregulation (SMD) versus healthy comparison (HC) youth. The tendency to allocate attention to threat is well established in anxiety and other disorders of negative affect. SMD is characterized by the negative affect of irritability, and longitudinal studies suggest childhood irritability predicts adult anxiety and depression. Therefore, it is important to study pathophysiologic connections between irritability and anxiety disorders. SMD patients (N = 74) and HC youth (N = 42) completed a visual probe paradigm to assess attention bias to emotional faces. Diagnostic interviews were conducted and measures of irritability and anxiety were obtained in patients. SMD youth differed from HC youth in having a bias toward threatening faces (P < .01). Threat bias was positively correlated with the severity of the SMD syndrome and depressive symptoms; degree of threat bias did not differ between SMD youth with and without co-occurring anxiety disorders or depression. SMD and HC youth did not differ in bias toward or away from happy faces. SMD youth demonstrate an attention bias toward threat, with greater threat bias associated with higher levels of SMD symptom severity. Our findings suggest that irritability may share a pathophysiological link with anxiety and depressive disorders. This finding suggests the value of exploring further whether attention bias modification treatments that are effective for anxiety are also helpful in the treatment of irritability.


[The mechanisms of motor learning].
In the paper the general principles of the motor learning are analyzed. A thesis is argued that instrumental conditioning is the basis of the motor learning, but the mechanisms of insight and the apparatus of anticipation of the action result also play an important role. At comparison of some theories of learning a hypothesis is suggested about the possibility of synthetic approach. Two stages can be distinguished in the process of the motor learning: formation of semantic and coordination programs. Formation and realization of learned movements opposite to the initial coordinations are constantly controlled by the motor cortex, which realizes the learned inhibition of the interfering coordinations.


MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance.
Molecule interacting with CasL2 (MICAL2), a microtubule-associated monooxygenase, is highly expressed in various cancers and is involved in cancer pathogenesis, but the mechanisms underlying its regulation in carcinogenesis are unclear. In this study, we aim to clarify the mechanism by which MICAL2 participates in colorectal cancer (CRC) and identify novel markers for predicting prognosis of CRC patients. Methods: The value of MICAL2 in CRC prognosis was determined by immunohistochemical analysis of a CRC biopsy array. A short hairpin RNA target MICAL2 (shMICAL2) was designed to knock down MICAL2 expression and observe MICAL2's function on CRC cell growth. mRNA expression array was used to screen target molecules of MICAL2. HCT116 p53+/+ and HCT116 p53-/- cells were used to confirm whether MICAL2 exerts its oncogenic effect through p53. The in vivo effect of MICAL2 on CRC growth was assessed by subcutaneously injecting MICAL2-knockout CRC cells into the dorsal flank of each mouse. Immunofluorescence was used to observe the effect of MICAL2 on p53 cellular location. Reverse-phase nano ESI-LCMS analysis was used to investigate if MICAL2 mediates p53 oxidation. Results: MICAL2 was found to be highly expressed in CRC tissues, and its expression was associated with CRC carcinogenesis and poor patient outcome. MICAL2-knockdown decreased growth and colony formation of CRC cells, which was linked with cell cycle arrest and apoptosis. MICAL2 physically interacted with p53 and retained p53 in the cytoplasm. MICAL2 shortened the half-life of p53, and ectopic MICAL2 expression decreased p53 protein stability through ubiquitin degradation. MICAL2 was also found to oxidize p53 at methionine 40 and 160, which mediated p53 ubiquitin degradation. MICAL2-promoted CRC growth in vivo was confirmed in nude mice. Conclusion: MICAL2 binds to p53, retains p53 in the cytoplasm and oxidizes it at Met 40 and 160, promotes p53 ubiquitination, and decreases p53 function. MICAL2-reduced p53 promotes CRC development.


[Nephrectomy in general surgical hospital].
In the central regional hospital 50 nephrectomies were performed for traumas and different diseases of the kidney, 44 of them being fulfilled through a laparoscopic access. This access allowed the volume of operation to be expanded in 58% of the patients. In 8% of the patients massive hemorrhage took place. Four patients died. Nephrectomy following pretreatment of the renal vessels allows to reduce risk of the operation.